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From basic research to clinical development of MEK1/2 inhibitors for cancer therapy

From basic research to clinical development of MEK1/2 inhibitors for cancer therapy The Ras-dependent Raf/MEK/ERK1/2 mitogen-activated protein (MAP) kinase signaling pathway is a major regulator of cell proliferation and survival. Not surprisingly, hyperactivation of this pathway is frequently observed in human malignancies as a result of aberrant activation of receptor tyrosine kinases or gain-of-function mutations in RAS or RAF genes. Components of the ERK1/2 pathway are therefore viewed as attractive candidates for the development of targeted therapies of cancer. In this article, we briefly review the basic research that has laid the groundwork for the clinical development of small molecules inhibitors of the ERK1/2 pathway. We then present the current state of clinical evaluation of MEK1/2 inhibitors in cancer and discuss challenges ahead. Introduction kinases, cytokine receptors or G protein-coupled recep- Human tumorigenesis is a multistep process during tors. Typically, ligand binding to receptor tyrosine which accumulation of genetic and epigenetic alterations kinases induces dimerization of the receptor and auto- leads to the progressive transformation of a normal cell phosphorylation of specific tyrosine residues in the into a malignant cancer cell. During this process, cancer C-terminal region. This generates binding sites for adap- cells acquire new capabilities (hallmarks) that enable tor proteins, such as growth factor receptor-bound pro- them to escape from normal homeostatic regulatory tein 2 (GRB2), which recruit the guanine nucleotide defensemechanisms. Thesehallmarks aredefined as: exchange factor Sos at the plasma membrane. Sos acti- self-sufficiency in growth signals, insensitivity to antipro- vates the membrane-bound Ras by catalyzing the repla- liferative signals, evasion from apoptosis, limitless repli- cement of GDP with GTP. In its GTP-bound form, Ras cative potential, sustained angiogenesis, and increased recruits Raf kinases (ARAF, BRAF and CRAF) to the motility and invasiveness [1]. While the mechanisms by plasma membrane, where they become activated by a which cancer cells acquire these capabilities vary consid- complex interplay of phosphorylation events and pro- erably between tumors of different types, most if not all tein-protein interactions. Raf acts as a MAP kinase of these physiological changes involve alteration of sig- kinase kinase (MAPKKK) and activates the MAP kinase nal transduction pathways. Among the signaling path- kinases (MAPKKs) MEK1 and MEK2, which, in turn, ways most frequently dysregulated in human cancer is catalyze the activation of the effector MAP kinases the Ras-Raf-MEK-extracellular signal-regulated kinase 1 ERK1 and ERK2 [3]. Once activated, ERK1/ERK2 phos- and 2 (ERK1/2) pathway. phorylate a panoply of nuclear and cytoplasmic sub- The Ras-dependent ERK1/2 mitogen-activated protein strates involved in diverse cellular responses, such as (MAP) kinase pathway is one of the best-studied signal cell proliferation, survival, differentiation, motility, and transduction pathways (Fig. 1). Since the discovery of angiogenesis [4]. MAP kinases by Ray and Sturgill in 1988 [2], more than 11,000 articles have been published on this topic. ERK1/ MEK1/MEK2 and the family of MAP kinase kinases 2 MAP kinases are activated by virtually all growth fac- MEK1 and MEK2 belong to the family of MAPKKs (also tors and cytokines acting through receptor tyrosine known as MEKs or MKKs), which are dual specificity enzymes that phosphorylate threonine and tyrosine resi- dues within the activation loop of their MAP kinase * Correspondence: sylvain.meloche@umontreal.ca Institut de Recherche en Immunologie et Cancérologie and Departments of substrates [5]. The human genome encodes seven Pharmacology and Molecular Biology, Université de Montréal, Montreal, MAPKK enzymes that regulate the activity of four Quebec H3C 3J7, Canada © 2010 Frémin and Meloche; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 2 of 11 http://www.jhoonline.org/content/3/1/8 Figure 1 Schematic representation of the Ras-Raf-MEK-ERK1/2 MAP kinase pathway. The figure shows the cascade of activation of the MAP kinases ERK1/ERK2 mediated by growth factor binding to receptor tyrosine kinases. See text for details. GF, growth factor; RTK, receptor tyrosine kinase. distinct MAP kinase pathways (Fig. 2A). Aside from activated receptor g (PPARg)toinduceits nuclear MEK1/MEK2, the MAPKKs MKK4 and MKK7 phos- export and attenuate its transcriptional activity [9]. phorylate and activate thec-Jun N-terminal kinase The high sequence identity between MEK1 and (JNK) isoforms, MKK3 and MKK6 phosphorylate and MEK2, and their significant similarity with MEK5 have activate the p38 isoforms, and MEK5 selectively acti- important pharmacological implications. First, this vates ERK5. Depending on the cellular context, MKK4 explains why small molecule MEK1/2 inhibitors devel- may also contribute to the activation of the p38 pathway oped so far are non-selective with regard to MEK1 and [6,7]. MEK2 isoforms. Structurally, MAPKKs are proteins of ~45-50 kDa that Although it is commonly believedthatthe two share 37-44% amino acid identity with MEK1/MEK2 in MAPKK isoforms are functionally equivalent, there is thekinasedomain(Fig. 2B). MEK1 andMEK2are evidence, however, that they are regulated differentially themselves 86% identical in the catalytic domain. In and may not be interchangeable in all cellular contexts addition to their kinase domain, MEK1 and MEK2 con- [10-13]. Intriguingly, it has been reported that activated tain a strong leucine-rich nuclear export signal (NES) at MEK1 but not MEK2 induces epidermal hyperplasia in their N-terminal extremity [8], a feature not found in transgenic mice [14]. RNA interference and gene invali- other MAPKK family members. Contrary to MAP dation studies have also suggested that MEK1 and kinases, MAPKKs have very narrow substrate specificity. MEK2 may contribute differentially to tumorigenesis It is assumed, from lack of evidence to the contrary, [15,16]. The physiopathological relevance of these obser- that the MAP kinases ERK1/ERK2 are the only sub- vations to human cancer remains unclear. Second, it strates of MEK1 and MEK2. However, the possibility helps understand why the first-generation MEK1/2 inhi- that MEK1/MEK2 have other non-catalytic effectors bitors PD98059, U0126 and PD184352 were also found cannot be excluded. For example, a recent study showed to inhibit MEK5 and the ERK5 MAP kinase pathway at that MEK1 interacts with peroxisome proliferator- higher concentrations [17,18]. Elucidation of the crystal Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 3 of 11 http://www.jhoonline.org/content/3/1/8 Figure 2 The MAP kinase kinases family. (A) MAP kinases and their upstream MAPKKs. (B) Schematic representation of human MAPKKs. MAPKKs are composed of a kinase catalytic domain (in blue) flanked by N- and C-terminus extensions of varying lengths. The percentage of identity of the kinase domain with MEK1 is indicated. An NES, only present in MEK1 and MEK2, is indicated in yellow. structures of MEK1 and MEK2 has revealed that MEK5 kinase-dead mutants of ERK1 or anti-sense ERK1 RNA share 83% amino acid identity with MEK1 in the inhibited the activation of ERK1/ERK2 and exerted a PD184352-like inhibitor-binding pocket [19]. These dominant-negative effect on cell proliferation [24]. MEK1/2 inhibitors have been used in thousands of These early findings were confirmed by subsequent papers and have proven extremely useful tools to inves- RNA interference-based studies showing that silencing tigate the biological functions of the ERK1/2 MAP of ERK1/ERK2 expression inhibits the proliferation of kinase pathway. However, their inhibitory activity various cell types [25-27]. Fourth, treatment with small towards MEK5, albeit weaker, indicates that we should molecule inhibitors of MEK1/MEK2 was reported to be cautious in the interpretation of data obtained at inhibit the proliferation of a variety of cell types [28-30]. high concentrations of inhibitor. Reciprocally, expression of constitutively-active forms of MEK1 was sufficient to stimulate cell proliferation and The ERK1/2 MAP kinase pathway is a key relax growth factor dependency [31-33]. Further demon- regulator of cell proliferation and survival stration of the essential role of ERK1/2 signaling in cell Multiple lines of evidence have implicated the ERK1/2 proliferation was provided by gene invalidation studies MAP kinase pathway in the control of cell proliferation in mice showing that loss of Erk1 or Erk2 gene function [20]. First, ERK1 and ERK2 are activated in response to results in impaired proliferation of specific cell types virtually all mitogenic factors. Second, several studies [34-37]. have reported that the mitogenic response to growth ERK1/2 signaling is required for the progression of factors is correlated with their ability to induce sus- cells from the G0/G1 to S phase [20,38]. Activation of tained ERK1/2 activity [21-23]. Third, expression of the ERK1/2 pathway is associated with induction of the Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 4 of 11 http://www.jhoonline.org/content/3/1/8 positive cell cycle regulators cyclin D1 [39] and c-Myc studies using clinical specimens have documented the [40], and with down-regulation of anti-proliferative pro- hyperactivation of MEK1/MEK2 and ERK1/ERK2 in teins such as Tob1 [23], Foxo3a [41] and p21 [42]. In solid tumor and hematological malignancies [61,62]. addition to its direct role in the cell division cycle, the Studies in cultured cells have revealed that expression ERK1/2 MAP kinase pathway also regulates cell growth of activated alleles of MEK1 or MEK2 is sufficient to by stimulating protein and nucleotide biosynthesis deregulate the proliferation and trigger transformation of [20,43]. One mechanism by which the ERK1/2 pathway immortalized fibroblast and epithelial cell lines increases global protein translation is through phosphor- [15,31,32,63,64]. Orthotopic transplantation of mammary ylation and inactivation of tuberin (also known as or intestinal epithelial cells expressing activated MEK1/ TSC2), a negative regulator of the master growth regula- MEK2 into mice induces the formation of aggressive tor mammalian target of rapamycin (mTOR), resulting tumors that progress up to the metastatic stage [15,64]. in increased mTOR signaling [44,45]. Similarly, expression of activated Raf mutants in various Studies in several experimental systems have high- cell lines, including melanocytes, stimulates MEK1/2 and lighted the important role of the Raf-MEK-ERK1/2 ERK1/2 signaling, and induces the formation of tumors MAP kinase pathway in the control of cell survival in nude mice [65]. The oncogenic activity of the Raf- [46,47]. Early studies have shown that activation of the MEK-ERK1/2 pathway was further tested in transgenic ERK1/2 pathway prevents apoptosis induced by growth mouse models. Transgenic expression of activated MEK1 factor withdrawal, loss of matrix attachment or cytoske- in mouse skin induces hyperproliferative and inflamma- letal disruption in cultured cells [48-51]. These findings tory lesions and inhibits epidermal differentiation, were reinforced by genetic studies showing that loss of mimicking features of squamous cell carcinomas ERK1/ERK2 or MEK1/MEK2 induces cell death in var- [14,66,67]. In the same way, targeted expression of acti- ious mouse tissues [37,52,53]. ERK1/2 signaling pro- vated forms of C-Raf or B-Raf in various tissues of trans- motes cell survival by repressing the expression or genic mice was shown to drive lung, skin, thyroid, and activity of pro-apoptotic Bcl-2 family proteins, such as prostate tumorigenesis [65,68,69]. Importantly, deinduc- Bim and Bad, and by inducing the expression of pro- tion of activated B-Raf expression in a conditional lung survival members like Bcl-2 and Mcl-1 [47]. cancer mouse model leads to dramatic tumor regression concomitant to inactivation of ERK1/2 signaling, sug- Hyperactivation of the ERK1/2 MAP kinase gesting a dependency of B-Raf-induced lung tumors on pathway in cancer the ERK1/2 pathway [70]. Given the central role of the Raf-MEK-ERK1/2 signaling Pre-clinical pharmacological studies have demon- pathway in cell proliferation and survival signaling, it is stratedthatblockadeofthe ERK1/2 pathwaywith therefore not surprising that alterations in this pathway small-molecule MEK1/2 inhibitors markedly restrains are highly prevalent in human cancer. Multiple genetic the proliferation of various carcinoma and leukemic cell changes can lead to hyperactivation of the ERK1/2 path- lines by inducing cell cycle arrest and apoptosis way in cancer (Fig. 3). Aberrant activation of receptor [28,30,71,72]. In vivo studies further established that tyrosine kinases such as the epidermal growth factor administration of orally available MEK1/2 inhibitors eli- (EGF) receptor, as a result of gene amplification or gain- cits significant tumor regression in mouse xenograft of-function mutations, is frequently observed in carcino- models [30,72-74]. The strategic position of MEK1 and mas and brain tumors [54,55]. Activating mutations in MEK2 in the Ras-dependent ERK1/2 pathway in con- RAS genes, most often in KRAS, are found in ~30% of junction with a promising pre-clinical profile have pro- cancers and are generally acquired early in the tumori- vided strong rationale for the development of small- genic process [56]. More recently, large-scale resequen- molecule inhibitors of MEK1/2 for chemotherapeutic cing studies have revealed that BRAF is mutated in intervention in cancer [62]. ~20% of all cancers and in more than 40% of melano- mas [57]. The majority of these mutations are clustered Clinical development of MEK1/2 inhibitors in the kinase domain of B-Raf and lead to the stimula- PD98059 was the first small-molecule inhibitor of tion of ERK1/2 activity in cells [58]. It is noteworthy MEK1/2 to be disclosed in 1995 [28]. Biochemical stu- that RAS and BRAF mutations are generally mutually dies indicated that PD98059 inhibits the activity of both exclusive in tumors, suggesting an epistatic relationship. MEK1 and MEK2 isoforms, but fails to inhibit a panel Also, activating mutations in MEK1 gene are found at of other Ser/Thr kinases [75,76]. Two other potent inhi- low prevalence in lung carcinomas, melanomas and bitors of MEK1/2, U0126 [77] and Ro 09-2210 [78], colon carcinomas [59,60]. However, no mutation in the were subsequently identified in cell-based assays. None ERK1 or ERK2 gene has been reported to date in of these compounds was moved to clinical evaluation tumors. Consistent with these observations, numerous because of their pharmaceutical limitations. However, Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 5 of 11 http://www.jhoonline.org/content/3/1/8 Figure 3 Genetic alterations of the Ras-dependent ERK1/2 pathway in cancer. PD98059 and U0126 have proven to be invaluable aca- inhibit the growth of colon carcinomas by as much as demic research tools to investigate the role of the 80% in mouse xenograft models [30]. Importantly, anti- ERK1/2 MAP kinase pathway in normal cell physiology tumor activity was achieved at well-tolerated doses and and disease. correlated with a reduction in the levels of phosphory- To date, eleven MEK1/2 inhibitors have been tested lated ERK1/2 in excised tumors. clinically or are currently undergoing clinical trial eva- A phase I study of orally administered CI-1040 was luation (Table 1). The chemical structures of some of undertaken in 77 patients with advanced cancers [79]. these inhibitors are given in Fig. 4. Results of this study indicated that the compound was CI-1040 (PD184352) Table 1 Small molecule MEK1/2 inhibitors in clinical trials The benzhydroxamate derivative CI-1040 (Pfizer) was Inhibitor Company Phase Status the first MEK1/2 inhibitor to enter clinical trials [79]. CI-1040 Pfizer Phase II Development CI-1040 is a potent (IC of 17 nM on purified MEK1) stopped and highly selective inhibitor of MEK1 and MEK2 that PD0325901 Pfizer Phase I/ Development was identified by screening a library compound with an II stopped in vitro ERK1 reactivation assay [30]. Similar to AZD6244 Array BioPharma/ Phase II In progress AstraZeneca PD98059 and U0126, CI-1040 and its analogs inhibit GDC-0973 Exelixis/ Phase I In progress MEK1/2 in a non-ATP and non-ERK1/2 competitive Genentech manner. Structural studies have revealed that CI-1040- RDEA119 Ardea Biosciences/ Phase I/ In progress related analogs bind into a hydrophobic pocket adjacent Bayer II to but not overlapping with the Mg-ATP binding site of GSK1120212 GlaxoSmithKline Phase I/ In progress MEK1 and MEK2 [19]. Binding of the inhibitor induces II a conformational change in unphosphorylated MEK1/2 AZD8330 Array BioPharma/ Phase I In progress AstraZeneca that locks the kinase into a close catalytically inactive RO5126766 Hoffmann La Roche Phase I In progress form. This binding pocket is located in a region with RO4987655 Hoffmann La Roche Phase I In progress low sequence homology to other kinases (except for TAK-733 Millenium Phase I In progress MEK5), which explains the high selectivity of these Pharmaceuticals compounds and their noncompetitive kinetics of inhibi- AS703026 EMD Serono Phase I In progress tion. In pre-clinical studies, CI-1040 was shown to Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 6 of 11 http://www.jhoonline.org/content/3/1/8 NH CN NH NH OMe NH CN NH PD098059 U0126 H H O N O N Cl F O OH H H N N OH I I F CI-1040 PD0325901 F F HO N O HO N O Cl Br AZD6244 AZD8330 OH OH O O H F I RDEA119 Figure 4 Chemical structures of small molecule MEK1/2 inhibitors. well tolerated at doses resulting in a median 73% inhibi- No patient achieved a complete or partial response, and tion of phospho-ERK1/2 expression in tumor biopsies. stabilization of disease (median of 4.4 months) was About 60% of patients experienced adverse effects, observed in only 8 patients. The insufficient antitumor mostly grade 1 or 2, with no patient having drug-related activity, poor solubility and low bioavailability of grade 4 events. The most common toxicities included CI-1040 precluded further clinical development of this diarrhea, asthenia, rash, nausea, and vomiting. Interest- compound. ingly, one patient with pancreatic cancer achieved a par- tial response with significant symptomatic improvement PD0325901 that lasted 12 months, and 19 additional patients suffer- The CI-1040 structural analogue PD0325901 (Pfizer) is a ing from a variety of cancers had disease stabilization second-generation MEK1/2 inhibitor with significantly lasting 4 to 17 months. This encouraging study provided improved pharmaceutical properties [81]. Optimization the first demonstration that MEK1/2 can be inhibited in of the diphenylamine core and modification of the hydro- vivo in humans, and the first evidence of clinical activity xamate side chain imparted PD0325901 with increases in for this class of agents. On this basis, a phase II study potency, solubility and bioavailability. PD0325901 has an was initiated in 67 patients with advanced breast, pan- IC value of 1 nM against purified MEK1/MEK2, and creatic, colon and non-small cell lung cancers [80]. inhibits the proliferation of various tumor cell lines at Unfortunately, results of this trial were disappointing. subnanomolar concentrations (100-fold more potent Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 7 of 11 http://www.jhoonline.org/content/3/1/8 than CI-1040) [62,72]. In vivo studies have demonstrated patients showed disease stabilization lasting for at least that PD0325901 potently inhibits the growth of human 5 months. tumor xenografts bearing activating mutations of B-Raf, Preliminary results from four randomized phase II concomitant with suppression of ERK1/2 phosphoryla- clinical trials of AZD6244 have been recently reported. tion [72]. The growth of Ras mutant tumors was also In a first study, AZD6244 was compared to the alkylat- inhibited partially. ing agent temozolomide in advanced melanoma patients. The clinical activity of PD0325901 was first evaluated Antitumor activity of AZD6244 was observed, but there in a phase I-II study of 35 patients with advanced solid was no significant difference in progression-free survival tumors employing a dose-escalating design [82,83]. between the two treatment arms [91]. A second study Doses ≥ 2 mg BID efficiently suppressed ERK1/2 phos- compared the efficacy of AZD6244 with the antimetabo- phorylation (average of 84%) and Ki67 expression (aver- lite pemetrexed as second- or third-line treatment of age of 60%) in tumor biopsies. Anticancer activity of patients with non-small cell lung cancer. Again, the PD0325901 was evaluated from 27 assessable patients. study showed evidence of single agent antitumor activ- Two partial responses were observed in melanoma ity, butfailedtodemonstrateadifferencefor thepri- patients, while 8 patients achieved stable disease lasting mary disease progression endpoint [92]. In a third study, 3-7 months [84]. The phase I study was extended and AZD6244 was compared to capecitabine in patients with clinical activity was documented by 3 partial responses metastatic colorectal cancer who had failed prior irino- in melanoma patients and 24 cases of disease stabiliza- tecan and/or oxaliplatin regimens. Similarly, no differ- tion (22 melanoma and 2 non-small cell lung cancer) in ence was observed between the two treatments in the 66 patients [85]. However, PD0325901 was associated number of patients with disease progression [93]. with more severe toxicity than CI-1040, including Finally, theresults of aphase II studyofAZD6244in blurred vision as well as acute neurotoxicity in patients patients with advanced or metastatic hepatocellular car- receiving more than 15 mg BID of the drug. The clinical cinoma were recently reported. The study was stopped development of this drug has been discontinued in 2008. prematurely due to the lack of radiographic response [94]. Other phase II trials are currently ongoing in a AZD6244 (ARRY-142886) variety of tumor types. The benzimidazole derivative AZD6244 (Array Bio- Pharma/AstraZeneca) is another second-generation GDC-0973 (XL518) potent inhibitor of MEK1/MEK2 [86]. AZD6244 selec- GDC-0973 (Exelixis/Genentech) is a potent, selective, tively inhibits purified active MEK1 and MEK2 with an orally active inhibitor of MEK1/2 with an IC of <1 nM IC of 14 nM by a mechanism not competitive with in vitro [95]. In cellular studies, the compound inhibits ATP. In cellular assays, the compound inhibits basal ERK1/2 phosphorylation at subnanomolar concentra- and growth factor-stimulated phosphorylation of ERK1/ tions, and exerts antiproliferative effects in multiple 2 with IC concentrations < 40 nM, and exerts antipro- tumor cell lines harboring KRAS or BRAF mutations. In liferative effects on tumor cell lines harboring BRAF or vivo pharmacodynamic studies have shown that a single RAS mutations [86-88]. AZD6244 has demonstrated oral dose of GDC-0973 inhibits phospho-ERK1/2 in potent dose-dependent antitumor activity against a tumors for up to 48 hours, translating into potent inhi- panel of mouse xenograft models of colorectal, pancrea- bition of tumor growth in human xenograft models. tic, liver, skin, and lung cancer [86-89]. Inhibition of Notably, GDC-0973 appears to have reduced activity in tumor growth was found tocorrelate with the reduction the brain, which may reduce the potential of central of phospho-ERK1/2 levels in tumors. Based on promis- nervous system side effects. A phase I dose-escalating ing pre-clinical activity, AZD6244 was advanced into study of GDC-0973 was initiated in subjects with solid clinical development. tumors. Preliminary results from 13 patients indicates A phase I clinical trial was undertaken to assess the that GDC-0973 is well tolerated with no drug-related safety, pharmacokinetics and pharmacodynamics of serious adverse events being reported [96]. One patient AZD6244 in 57 patients with advanced cancer [90]. with non-small cell lung cancer had stabilization of dis- Results of this study showed that the 50% maximal tol- ease for 7 months and continues on treatment. Another erated dose (100 mg BID) was well tolerated with skin phase I trial of GDC-0973 in combination with the rash being the most frequent and dose-limiting toxicity. phosphatidylinositol 3-kinase (PI3K) inhibitor GDC- Most other adverse events were of grade 1 or 2. Nota- 0941 is planned. bly, 7 patients developed transient and reversible blurred vision, an adverse effect also observed with PD0325901. RDEA119 (BAY 869766) A strong reduction in ERK1/2 phosphorylation (mean RDEA119 (Ardea Biosciences/Bayer) is another orally inhibition of 79%) was observed in tumor biopsies. Nine available, allosteric inhibitor of MEK1/2 [97]. In vitro, Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 8 of 11 http://www.jhoonline.org/content/3/1/8 RDEA119 selectively inhibits MEK1 (IC of 19 nM) and whether blocking the pathway at the level of Raf is a clini- MEK2 (IC of 47 nM) in a non-ATP competitive man- cally viable approach. Inhibitors of MEK1/2 are highly ner. Cellular assays showed that RDEA119 potently inhi- selective for their targets. However, results from the first bits ERK1/2 phosphorylation (IC from 2.5 to 16 nM) clinical trials have been disappointing. New MEK1/2 inhi- and cell proliferation in a panel of human cancer cell bitors with improved pharmaceutical properties and lines. In vivo, RDEA119 exhibits potent antitumor activ- reduced central nervous system activity are promising and ity in xenograft models of human melanoma, colon and results of ongoing trials are anxiously awaited. epidermal carcinoma. Interestingly, pharmacodynamic As for other targeted therapies, several outstanding studies have revealed that the compound has low central questions remain to be addressed before MEK1/2 inhibi- nervous system penetration. RDEA119 is currently being tors join the arsenal of anticancer drugs. Which patients evaluated as single agent in a phase I study in advanced are more likely to benefit from MEK1/2 inhibitors? Pre- cancer patients, and in a phase I/II study in combination clinical studies suggest that patients harboring activating with the multikinase and Raf inhibitor sorafenib. mutations in RAS or BRAF genes are better candidates for treatment with these kinase inhibitors. Thus, selection GSK1120212 of appropriate patient populations based on genetic GSK1120212 (GlaxoSmithKline) is an orally available, lesions or validated biochemical markers will be critical selective inhibitor of MEK1/2 with reported antitumor for future clinical trial evaluation. Is the therapeutic effi- activity in mouse xenograft models [98]. A phase I study cacy of MEK1/2 inhibitors hampered by dose-limiting of GSK1120212 was undertaken in 2008 in patients with toxicity? The ubiquitous involvement of the ERK1/2 solid tumors and lymphoma. Preliminary evaluation of 6 MAP kinase pathway in cellular responses has raised patients treated at four dose levels indicates that concern about the potential toxicity of drugs blocking GSK1120212 is well tolerated with no dose-limiting this pathway. The ocular toxicity observed with toxicity reported so far [98]. Dose escalation is ongoing. PD0325901 and AZD6244 suggests the existence of Two other phase I/II studies of GSK1120212 have been mechanism-based adverse effects. Interestingly, new recently initiated in subjects with relapsed or refractory MEK1/2 inhibitors such as GDC-0973 and RDEA119 leukemias, and in combination with everolimus in have reduced activity in the brain, which may increase patients with solid tumors. their therapeutic window. What are the most rationale and best combination therapies with MEK1/2 inhibitors? OTHER MEK1/2 INHIBITORS The multigenetic nature of advanced cancers suggests Five other MEK1/2 inhibitors are currently being evalu- that MEK1/2 inhibitors will likely find their therapeutic ated in phase I clinical trials in advanced cancer utility in combination with other targeted agents or con- patients. These are AZD8330 (Array BioPharma/Astra- ventional cytotoxic drugs. Pre-clinical studies have Zeneca), RO5126766 and RO4987655 (Hoffmann La shown that PI3K pathway activation, through PIK3CA Roche), TAK-733 (Millenium Pharmaceuticals) and activating mutations or PTEN loss of function, signifi- AS703026 (EMD Serono). Other novel MEK1/2 inhibi- cantly decreases the response of KRAS mutant cancer tors such as RO4927350 and RO5068760 have recently cells to MEK1/2 inhibitors [102]. Importantly, simulta- been reported but have not yet passed the pre-clinical neous inhibition of the ERK1/2 and PI3K pathways was stage [99,100]. found to exert a marked synergistic effect on tumor regression [102,103]. These observations have provided a Concluding remarks and challenges strong rationale for the combination of MEK1/2 and Despite strong rationale for the clinical development of PI3K inhibitors in cancers that harbor concurrent activat- drugs targeting the ERK1/2 MAP kinase pathway in can- ing mutations in these signaling pathways. In that con- cer, the effectiveness of this approach in cancer therapy text, Merck and AstraZeneca have recently announced remains to be validated. The first and only inhibitor of the their plan to collaborate in testing a combination therapy ERK1/2 pathway that has received regulatory approval for of AZD6244 and the Akt inhibitor MK-2206 in cancer the treatment of advanced renal cell carcinoma and hepa- [104]. Finally, is the acquisition of resistance mutations in tocellular carcinoma is the Raf inhibitor sorafenib (Nexa- MEK1/MEK2 going to limit the clinical utility of these var) [101]. However, sorafenib is a multikinase inhibitor small molecule inhibitors? A recent study has reported that also inhibits the vascular endothelial growth factor the identification of a resistant MEK1 mutation in a and platelet-derived growth factor receptor tyrosine metastatic tumor that emerged in a melanoma patient kinases, as well as Flt-3 and c-Kit receptors. To what treated with AZD6244 [105]. Therefore, it may prove extent the inhibition of Raf signaling contributes to the necessary to target other components of the ERK1/2 clinical activity of the drug is not clear. Future clinical pathway in patients who develop resistance or, even- trials of more selective Raf inhibitors will help determine tually, to combine MEK1/2 inhibitors with Raf inhibitors Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 9 of 11 http://www.jhoonline.org/content/3/1/8 cells and induce the formation of metastatic tumors. BMC Cancer 2008, to slow down the emergence of resistance. A phase I/II 8:337. study of RDEA119 in combination with the multikinase 16. Scholl FA, Dumesic PA, Barragan DI, Charron J, Khavari PA: Mek1/2 gene Raf inhibitor sorafenib is currently ongoing. dosage determines tissue response to oncogenic Ras signaling in the skin. Oncogene 2009, 28:1485-1495. 17. 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Johnston S: XL518, a potent, selective orally bioavailable MEK1 inhibitor, • Convenient online submission down-regulates the Ras/Raf/MEK/ERK pathway in vivo, resulting in tumor growth inhibition and regression in preclinical models. 19th AACR- • Thorough peer review NCI-EORTC International Conference on Molecular Targets and Cancer • No space constraints or color figure charges Therapeutics 2007, Abstract C209. • Immediate publication on acceptance 96. Rosen LS, Galatin P, Fehling JM, Laux I, Dinolfo M, Frye J, Laird D, Sikic BI: A phase 1 dose-escalation study of XL518, a potent MEK inhibitor • Inclusion in PubMed, CAS, Scopus and Google Scholar administered orally daily to subjects with solid tumors. J Clin Oncol • Research which is freely available for redistribution (abstract) 2008, 26:14585. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Hematology & Oncology Springer Journals

From basic research to clinical development of MEK1/2 inhibitors for cancer therapy

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Springer Journals
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Copyright © 2010 by Frémin and Meloche; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Hematology; Cancer Research
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1756-8722
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10.1186/1756-8722-3-8
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20149254
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Abstract

The Ras-dependent Raf/MEK/ERK1/2 mitogen-activated protein (MAP) kinase signaling pathway is a major regulator of cell proliferation and survival. Not surprisingly, hyperactivation of this pathway is frequently observed in human malignancies as a result of aberrant activation of receptor tyrosine kinases or gain-of-function mutations in RAS or RAF genes. Components of the ERK1/2 pathway are therefore viewed as attractive candidates for the development of targeted therapies of cancer. In this article, we briefly review the basic research that has laid the groundwork for the clinical development of small molecules inhibitors of the ERK1/2 pathway. We then present the current state of clinical evaluation of MEK1/2 inhibitors in cancer and discuss challenges ahead. Introduction kinases, cytokine receptors or G protein-coupled recep- Human tumorigenesis is a multistep process during tors. Typically, ligand binding to receptor tyrosine which accumulation of genetic and epigenetic alterations kinases induces dimerization of the receptor and auto- leads to the progressive transformation of a normal cell phosphorylation of specific tyrosine residues in the into a malignant cancer cell. During this process, cancer C-terminal region. This generates binding sites for adap- cells acquire new capabilities (hallmarks) that enable tor proteins, such as growth factor receptor-bound pro- them to escape from normal homeostatic regulatory tein 2 (GRB2), which recruit the guanine nucleotide defensemechanisms. Thesehallmarks aredefined as: exchange factor Sos at the plasma membrane. Sos acti- self-sufficiency in growth signals, insensitivity to antipro- vates the membrane-bound Ras by catalyzing the repla- liferative signals, evasion from apoptosis, limitless repli- cement of GDP with GTP. In its GTP-bound form, Ras cative potential, sustained angiogenesis, and increased recruits Raf kinases (ARAF, BRAF and CRAF) to the motility and invasiveness [1]. While the mechanisms by plasma membrane, where they become activated by a which cancer cells acquire these capabilities vary consid- complex interplay of phosphorylation events and pro- erably between tumors of different types, most if not all tein-protein interactions. Raf acts as a MAP kinase of these physiological changes involve alteration of sig- kinase kinase (MAPKKK) and activates the MAP kinase nal transduction pathways. Among the signaling path- kinases (MAPKKs) MEK1 and MEK2, which, in turn, ways most frequently dysregulated in human cancer is catalyze the activation of the effector MAP kinases the Ras-Raf-MEK-extracellular signal-regulated kinase 1 ERK1 and ERK2 [3]. Once activated, ERK1/ERK2 phos- and 2 (ERK1/2) pathway. phorylate a panoply of nuclear and cytoplasmic sub- The Ras-dependent ERK1/2 mitogen-activated protein strates involved in diverse cellular responses, such as (MAP) kinase pathway is one of the best-studied signal cell proliferation, survival, differentiation, motility, and transduction pathways (Fig. 1). Since the discovery of angiogenesis [4]. MAP kinases by Ray and Sturgill in 1988 [2], more than 11,000 articles have been published on this topic. ERK1/ MEK1/MEK2 and the family of MAP kinase kinases 2 MAP kinases are activated by virtually all growth fac- MEK1 and MEK2 belong to the family of MAPKKs (also tors and cytokines acting through receptor tyrosine known as MEKs or MKKs), which are dual specificity enzymes that phosphorylate threonine and tyrosine resi- dues within the activation loop of their MAP kinase * Correspondence: sylvain.meloche@umontreal.ca Institut de Recherche en Immunologie et Cancérologie and Departments of substrates [5]. The human genome encodes seven Pharmacology and Molecular Biology, Université de Montréal, Montreal, MAPKK enzymes that regulate the activity of four Quebec H3C 3J7, Canada © 2010 Frémin and Meloche; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 2 of 11 http://www.jhoonline.org/content/3/1/8 Figure 1 Schematic representation of the Ras-Raf-MEK-ERK1/2 MAP kinase pathway. The figure shows the cascade of activation of the MAP kinases ERK1/ERK2 mediated by growth factor binding to receptor tyrosine kinases. See text for details. GF, growth factor; RTK, receptor tyrosine kinase. distinct MAP kinase pathways (Fig. 2A). Aside from activated receptor g (PPARg)toinduceits nuclear MEK1/MEK2, the MAPKKs MKK4 and MKK7 phos- export and attenuate its transcriptional activity [9]. phorylate and activate thec-Jun N-terminal kinase The high sequence identity between MEK1 and (JNK) isoforms, MKK3 and MKK6 phosphorylate and MEK2, and their significant similarity with MEK5 have activate the p38 isoforms, and MEK5 selectively acti- important pharmacological implications. First, this vates ERK5. Depending on the cellular context, MKK4 explains why small molecule MEK1/2 inhibitors devel- may also contribute to the activation of the p38 pathway oped so far are non-selective with regard to MEK1 and [6,7]. MEK2 isoforms. Structurally, MAPKKs are proteins of ~45-50 kDa that Although it is commonly believedthatthe two share 37-44% amino acid identity with MEK1/MEK2 in MAPKK isoforms are functionally equivalent, there is thekinasedomain(Fig. 2B). MEK1 andMEK2are evidence, however, that they are regulated differentially themselves 86% identical in the catalytic domain. In and may not be interchangeable in all cellular contexts addition to their kinase domain, MEK1 and MEK2 con- [10-13]. Intriguingly, it has been reported that activated tain a strong leucine-rich nuclear export signal (NES) at MEK1 but not MEK2 induces epidermal hyperplasia in their N-terminal extremity [8], a feature not found in transgenic mice [14]. RNA interference and gene invali- other MAPKK family members. Contrary to MAP dation studies have also suggested that MEK1 and kinases, MAPKKs have very narrow substrate specificity. MEK2 may contribute differentially to tumorigenesis It is assumed, from lack of evidence to the contrary, [15,16]. The physiopathological relevance of these obser- that the MAP kinases ERK1/ERK2 are the only sub- vations to human cancer remains unclear. Second, it strates of MEK1 and MEK2. However, the possibility helps understand why the first-generation MEK1/2 inhi- that MEK1/MEK2 have other non-catalytic effectors bitors PD98059, U0126 and PD184352 were also found cannot be excluded. For example, a recent study showed to inhibit MEK5 and the ERK5 MAP kinase pathway at that MEK1 interacts with peroxisome proliferator- higher concentrations [17,18]. Elucidation of the crystal Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 3 of 11 http://www.jhoonline.org/content/3/1/8 Figure 2 The MAP kinase kinases family. (A) MAP kinases and their upstream MAPKKs. (B) Schematic representation of human MAPKKs. MAPKKs are composed of a kinase catalytic domain (in blue) flanked by N- and C-terminus extensions of varying lengths. The percentage of identity of the kinase domain with MEK1 is indicated. An NES, only present in MEK1 and MEK2, is indicated in yellow. structures of MEK1 and MEK2 has revealed that MEK5 kinase-dead mutants of ERK1 or anti-sense ERK1 RNA share 83% amino acid identity with MEK1 in the inhibited the activation of ERK1/ERK2 and exerted a PD184352-like inhibitor-binding pocket [19]. These dominant-negative effect on cell proliferation [24]. MEK1/2 inhibitors have been used in thousands of These early findings were confirmed by subsequent papers and have proven extremely useful tools to inves- RNA interference-based studies showing that silencing tigate the biological functions of the ERK1/2 MAP of ERK1/ERK2 expression inhibits the proliferation of kinase pathway. However, their inhibitory activity various cell types [25-27]. Fourth, treatment with small towards MEK5, albeit weaker, indicates that we should molecule inhibitors of MEK1/MEK2 was reported to be cautious in the interpretation of data obtained at inhibit the proliferation of a variety of cell types [28-30]. high concentrations of inhibitor. Reciprocally, expression of constitutively-active forms of MEK1 was sufficient to stimulate cell proliferation and The ERK1/2 MAP kinase pathway is a key relax growth factor dependency [31-33]. Further demon- regulator of cell proliferation and survival stration of the essential role of ERK1/2 signaling in cell Multiple lines of evidence have implicated the ERK1/2 proliferation was provided by gene invalidation studies MAP kinase pathway in the control of cell proliferation in mice showing that loss of Erk1 or Erk2 gene function [20]. First, ERK1 and ERK2 are activated in response to results in impaired proliferation of specific cell types virtually all mitogenic factors. Second, several studies [34-37]. have reported that the mitogenic response to growth ERK1/2 signaling is required for the progression of factors is correlated with their ability to induce sus- cells from the G0/G1 to S phase [20,38]. Activation of tained ERK1/2 activity [21-23]. Third, expression of the ERK1/2 pathway is associated with induction of the Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 4 of 11 http://www.jhoonline.org/content/3/1/8 positive cell cycle regulators cyclin D1 [39] and c-Myc studies using clinical specimens have documented the [40], and with down-regulation of anti-proliferative pro- hyperactivation of MEK1/MEK2 and ERK1/ERK2 in teins such as Tob1 [23], Foxo3a [41] and p21 [42]. In solid tumor and hematological malignancies [61,62]. addition to its direct role in the cell division cycle, the Studies in cultured cells have revealed that expression ERK1/2 MAP kinase pathway also regulates cell growth of activated alleles of MEK1 or MEK2 is sufficient to by stimulating protein and nucleotide biosynthesis deregulate the proliferation and trigger transformation of [20,43]. One mechanism by which the ERK1/2 pathway immortalized fibroblast and epithelial cell lines increases global protein translation is through phosphor- [15,31,32,63,64]. Orthotopic transplantation of mammary ylation and inactivation of tuberin (also known as or intestinal epithelial cells expressing activated MEK1/ TSC2), a negative regulator of the master growth regula- MEK2 into mice induces the formation of aggressive tor mammalian target of rapamycin (mTOR), resulting tumors that progress up to the metastatic stage [15,64]. in increased mTOR signaling [44,45]. Similarly, expression of activated Raf mutants in various Studies in several experimental systems have high- cell lines, including melanocytes, stimulates MEK1/2 and lighted the important role of the Raf-MEK-ERK1/2 ERK1/2 signaling, and induces the formation of tumors MAP kinase pathway in the control of cell survival in nude mice [65]. The oncogenic activity of the Raf- [46,47]. Early studies have shown that activation of the MEK-ERK1/2 pathway was further tested in transgenic ERK1/2 pathway prevents apoptosis induced by growth mouse models. Transgenic expression of activated MEK1 factor withdrawal, loss of matrix attachment or cytoske- in mouse skin induces hyperproliferative and inflamma- letal disruption in cultured cells [48-51]. These findings tory lesions and inhibits epidermal differentiation, were reinforced by genetic studies showing that loss of mimicking features of squamous cell carcinomas ERK1/ERK2 or MEK1/MEK2 induces cell death in var- [14,66,67]. In the same way, targeted expression of acti- ious mouse tissues [37,52,53]. ERK1/2 signaling pro- vated forms of C-Raf or B-Raf in various tissues of trans- motes cell survival by repressing the expression or genic mice was shown to drive lung, skin, thyroid, and activity of pro-apoptotic Bcl-2 family proteins, such as prostate tumorigenesis [65,68,69]. Importantly, deinduc- Bim and Bad, and by inducing the expression of pro- tion of activated B-Raf expression in a conditional lung survival members like Bcl-2 and Mcl-1 [47]. cancer mouse model leads to dramatic tumor regression concomitant to inactivation of ERK1/2 signaling, sug- Hyperactivation of the ERK1/2 MAP kinase gesting a dependency of B-Raf-induced lung tumors on pathway in cancer the ERK1/2 pathway [70]. Given the central role of the Raf-MEK-ERK1/2 signaling Pre-clinical pharmacological studies have demon- pathway in cell proliferation and survival signaling, it is stratedthatblockadeofthe ERK1/2 pathwaywith therefore not surprising that alterations in this pathway small-molecule MEK1/2 inhibitors markedly restrains are highly prevalent in human cancer. Multiple genetic the proliferation of various carcinoma and leukemic cell changes can lead to hyperactivation of the ERK1/2 path- lines by inducing cell cycle arrest and apoptosis way in cancer (Fig. 3). Aberrant activation of receptor [28,30,71,72]. In vivo studies further established that tyrosine kinases such as the epidermal growth factor administration of orally available MEK1/2 inhibitors eli- (EGF) receptor, as a result of gene amplification or gain- cits significant tumor regression in mouse xenograft of-function mutations, is frequently observed in carcino- models [30,72-74]. The strategic position of MEK1 and mas and brain tumors [54,55]. Activating mutations in MEK2 in the Ras-dependent ERK1/2 pathway in con- RAS genes, most often in KRAS, are found in ~30% of junction with a promising pre-clinical profile have pro- cancers and are generally acquired early in the tumori- vided strong rationale for the development of small- genic process [56]. More recently, large-scale resequen- molecule inhibitors of MEK1/2 for chemotherapeutic cing studies have revealed that BRAF is mutated in intervention in cancer [62]. ~20% of all cancers and in more than 40% of melano- mas [57]. The majority of these mutations are clustered Clinical development of MEK1/2 inhibitors in the kinase domain of B-Raf and lead to the stimula- PD98059 was the first small-molecule inhibitor of tion of ERK1/2 activity in cells [58]. It is noteworthy MEK1/2 to be disclosed in 1995 [28]. Biochemical stu- that RAS and BRAF mutations are generally mutually dies indicated that PD98059 inhibits the activity of both exclusive in tumors, suggesting an epistatic relationship. MEK1 and MEK2 isoforms, but fails to inhibit a panel Also, activating mutations in MEK1 gene are found at of other Ser/Thr kinases [75,76]. Two other potent inhi- low prevalence in lung carcinomas, melanomas and bitors of MEK1/2, U0126 [77] and Ro 09-2210 [78], colon carcinomas [59,60]. However, no mutation in the were subsequently identified in cell-based assays. None ERK1 or ERK2 gene has been reported to date in of these compounds was moved to clinical evaluation tumors. Consistent with these observations, numerous because of their pharmaceutical limitations. However, Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 5 of 11 http://www.jhoonline.org/content/3/1/8 Figure 3 Genetic alterations of the Ras-dependent ERK1/2 pathway in cancer. PD98059 and U0126 have proven to be invaluable aca- inhibit the growth of colon carcinomas by as much as demic research tools to investigate the role of the 80% in mouse xenograft models [30]. Importantly, anti- ERK1/2 MAP kinase pathway in normal cell physiology tumor activity was achieved at well-tolerated doses and and disease. correlated with a reduction in the levels of phosphory- To date, eleven MEK1/2 inhibitors have been tested lated ERK1/2 in excised tumors. clinically or are currently undergoing clinical trial eva- A phase I study of orally administered CI-1040 was luation (Table 1). The chemical structures of some of undertaken in 77 patients with advanced cancers [79]. these inhibitors are given in Fig. 4. Results of this study indicated that the compound was CI-1040 (PD184352) Table 1 Small molecule MEK1/2 inhibitors in clinical trials The benzhydroxamate derivative CI-1040 (Pfizer) was Inhibitor Company Phase Status the first MEK1/2 inhibitor to enter clinical trials [79]. CI-1040 Pfizer Phase II Development CI-1040 is a potent (IC of 17 nM on purified MEK1) stopped and highly selective inhibitor of MEK1 and MEK2 that PD0325901 Pfizer Phase I/ Development was identified by screening a library compound with an II stopped in vitro ERK1 reactivation assay [30]. Similar to AZD6244 Array BioPharma/ Phase II In progress AstraZeneca PD98059 and U0126, CI-1040 and its analogs inhibit GDC-0973 Exelixis/ Phase I In progress MEK1/2 in a non-ATP and non-ERK1/2 competitive Genentech manner. Structural studies have revealed that CI-1040- RDEA119 Ardea Biosciences/ Phase I/ In progress related analogs bind into a hydrophobic pocket adjacent Bayer II to but not overlapping with the Mg-ATP binding site of GSK1120212 GlaxoSmithKline Phase I/ In progress MEK1 and MEK2 [19]. Binding of the inhibitor induces II a conformational change in unphosphorylated MEK1/2 AZD8330 Array BioPharma/ Phase I In progress AstraZeneca that locks the kinase into a close catalytically inactive RO5126766 Hoffmann La Roche Phase I In progress form. This binding pocket is located in a region with RO4987655 Hoffmann La Roche Phase I In progress low sequence homology to other kinases (except for TAK-733 Millenium Phase I In progress MEK5), which explains the high selectivity of these Pharmaceuticals compounds and their noncompetitive kinetics of inhibi- AS703026 EMD Serono Phase I In progress tion. In pre-clinical studies, CI-1040 was shown to Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 6 of 11 http://www.jhoonline.org/content/3/1/8 NH CN NH NH OMe NH CN NH PD098059 U0126 H H O N O N Cl F O OH H H N N OH I I F CI-1040 PD0325901 F F HO N O HO N O Cl Br AZD6244 AZD8330 OH OH O O H F I RDEA119 Figure 4 Chemical structures of small molecule MEK1/2 inhibitors. well tolerated at doses resulting in a median 73% inhibi- No patient achieved a complete or partial response, and tion of phospho-ERK1/2 expression in tumor biopsies. stabilization of disease (median of 4.4 months) was About 60% of patients experienced adverse effects, observed in only 8 patients. The insufficient antitumor mostly grade 1 or 2, with no patient having drug-related activity, poor solubility and low bioavailability of grade 4 events. The most common toxicities included CI-1040 precluded further clinical development of this diarrhea, asthenia, rash, nausea, and vomiting. Interest- compound. ingly, one patient with pancreatic cancer achieved a par- tial response with significant symptomatic improvement PD0325901 that lasted 12 months, and 19 additional patients suffer- The CI-1040 structural analogue PD0325901 (Pfizer) is a ing from a variety of cancers had disease stabilization second-generation MEK1/2 inhibitor with significantly lasting 4 to 17 months. This encouraging study provided improved pharmaceutical properties [81]. Optimization the first demonstration that MEK1/2 can be inhibited in of the diphenylamine core and modification of the hydro- vivo in humans, and the first evidence of clinical activity xamate side chain imparted PD0325901 with increases in for this class of agents. On this basis, a phase II study potency, solubility and bioavailability. PD0325901 has an was initiated in 67 patients with advanced breast, pan- IC value of 1 nM against purified MEK1/MEK2, and creatic, colon and non-small cell lung cancers [80]. inhibits the proliferation of various tumor cell lines at Unfortunately, results of this trial were disappointing. subnanomolar concentrations (100-fold more potent Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 7 of 11 http://www.jhoonline.org/content/3/1/8 than CI-1040) [62,72]. In vivo studies have demonstrated patients showed disease stabilization lasting for at least that PD0325901 potently inhibits the growth of human 5 months. tumor xenografts bearing activating mutations of B-Raf, Preliminary results from four randomized phase II concomitant with suppression of ERK1/2 phosphoryla- clinical trials of AZD6244 have been recently reported. tion [72]. The growth of Ras mutant tumors was also In a first study, AZD6244 was compared to the alkylat- inhibited partially. ing agent temozolomide in advanced melanoma patients. The clinical activity of PD0325901 was first evaluated Antitumor activity of AZD6244 was observed, but there in a phase I-II study of 35 patients with advanced solid was no significant difference in progression-free survival tumors employing a dose-escalating design [82,83]. between the two treatment arms [91]. A second study Doses ≥ 2 mg BID efficiently suppressed ERK1/2 phos- compared the efficacy of AZD6244 with the antimetabo- phorylation (average of 84%) and Ki67 expression (aver- lite pemetrexed as second- or third-line treatment of age of 60%) in tumor biopsies. Anticancer activity of patients with non-small cell lung cancer. Again, the PD0325901 was evaluated from 27 assessable patients. study showed evidence of single agent antitumor activ- Two partial responses were observed in melanoma ity, butfailedtodemonstrateadifferencefor thepri- patients, while 8 patients achieved stable disease lasting mary disease progression endpoint [92]. In a third study, 3-7 months [84]. The phase I study was extended and AZD6244 was compared to capecitabine in patients with clinical activity was documented by 3 partial responses metastatic colorectal cancer who had failed prior irino- in melanoma patients and 24 cases of disease stabiliza- tecan and/or oxaliplatin regimens. Similarly, no differ- tion (22 melanoma and 2 non-small cell lung cancer) in ence was observed between the two treatments in the 66 patients [85]. However, PD0325901 was associated number of patients with disease progression [93]. with more severe toxicity than CI-1040, including Finally, theresults of aphase II studyofAZD6244in blurred vision as well as acute neurotoxicity in patients patients with advanced or metastatic hepatocellular car- receiving more than 15 mg BID of the drug. The clinical cinoma were recently reported. The study was stopped development of this drug has been discontinued in 2008. prematurely due to the lack of radiographic response [94]. Other phase II trials are currently ongoing in a AZD6244 (ARRY-142886) variety of tumor types. The benzimidazole derivative AZD6244 (Array Bio- Pharma/AstraZeneca) is another second-generation GDC-0973 (XL518) potent inhibitor of MEK1/MEK2 [86]. AZD6244 selec- GDC-0973 (Exelixis/Genentech) is a potent, selective, tively inhibits purified active MEK1 and MEK2 with an orally active inhibitor of MEK1/2 with an IC of <1 nM IC of 14 nM by a mechanism not competitive with in vitro [95]. In cellular studies, the compound inhibits ATP. In cellular assays, the compound inhibits basal ERK1/2 phosphorylation at subnanomolar concentra- and growth factor-stimulated phosphorylation of ERK1/ tions, and exerts antiproliferative effects in multiple 2 with IC concentrations < 40 nM, and exerts antipro- tumor cell lines harboring KRAS or BRAF mutations. In liferative effects on tumor cell lines harboring BRAF or vivo pharmacodynamic studies have shown that a single RAS mutations [86-88]. AZD6244 has demonstrated oral dose of GDC-0973 inhibits phospho-ERK1/2 in potent dose-dependent antitumor activity against a tumors for up to 48 hours, translating into potent inhi- panel of mouse xenograft models of colorectal, pancrea- bition of tumor growth in human xenograft models. tic, liver, skin, and lung cancer [86-89]. Inhibition of Notably, GDC-0973 appears to have reduced activity in tumor growth was found tocorrelate with the reduction the brain, which may reduce the potential of central of phospho-ERK1/2 levels in tumors. Based on promis- nervous system side effects. A phase I dose-escalating ing pre-clinical activity, AZD6244 was advanced into study of GDC-0973 was initiated in subjects with solid clinical development. tumors. Preliminary results from 13 patients indicates A phase I clinical trial was undertaken to assess the that GDC-0973 is well tolerated with no drug-related safety, pharmacokinetics and pharmacodynamics of serious adverse events being reported [96]. One patient AZD6244 in 57 patients with advanced cancer [90]. with non-small cell lung cancer had stabilization of dis- Results of this study showed that the 50% maximal tol- ease for 7 months and continues on treatment. Another erated dose (100 mg BID) was well tolerated with skin phase I trial of GDC-0973 in combination with the rash being the most frequent and dose-limiting toxicity. phosphatidylinositol 3-kinase (PI3K) inhibitor GDC- Most other adverse events were of grade 1 or 2. Nota- 0941 is planned. bly, 7 patients developed transient and reversible blurred vision, an adverse effect also observed with PD0325901. RDEA119 (BAY 869766) A strong reduction in ERK1/2 phosphorylation (mean RDEA119 (Ardea Biosciences/Bayer) is another orally inhibition of 79%) was observed in tumor biopsies. Nine available, allosteric inhibitor of MEK1/2 [97]. In vitro, Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 8 of 11 http://www.jhoonline.org/content/3/1/8 RDEA119 selectively inhibits MEK1 (IC of 19 nM) and whether blocking the pathway at the level of Raf is a clini- MEK2 (IC of 47 nM) in a non-ATP competitive man- cally viable approach. Inhibitors of MEK1/2 are highly ner. Cellular assays showed that RDEA119 potently inhi- selective for their targets. However, results from the first bits ERK1/2 phosphorylation (IC from 2.5 to 16 nM) clinical trials have been disappointing. New MEK1/2 inhi- and cell proliferation in a panel of human cancer cell bitors with improved pharmaceutical properties and lines. In vivo, RDEA119 exhibits potent antitumor activ- reduced central nervous system activity are promising and ity in xenograft models of human melanoma, colon and results of ongoing trials are anxiously awaited. epidermal carcinoma. Interestingly, pharmacodynamic As for other targeted therapies, several outstanding studies have revealed that the compound has low central questions remain to be addressed before MEK1/2 inhibi- nervous system penetration. RDEA119 is currently being tors join the arsenal of anticancer drugs. Which patients evaluated as single agent in a phase I study in advanced are more likely to benefit from MEK1/2 inhibitors? Pre- cancer patients, and in a phase I/II study in combination clinical studies suggest that patients harboring activating with the multikinase and Raf inhibitor sorafenib. mutations in RAS or BRAF genes are better candidates for treatment with these kinase inhibitors. Thus, selection GSK1120212 of appropriate patient populations based on genetic GSK1120212 (GlaxoSmithKline) is an orally available, lesions or validated biochemical markers will be critical selective inhibitor of MEK1/2 with reported antitumor for future clinical trial evaluation. Is the therapeutic effi- activity in mouse xenograft models [98]. A phase I study cacy of MEK1/2 inhibitors hampered by dose-limiting of GSK1120212 was undertaken in 2008 in patients with toxicity? The ubiquitous involvement of the ERK1/2 solid tumors and lymphoma. Preliminary evaluation of 6 MAP kinase pathway in cellular responses has raised patients treated at four dose levels indicates that concern about the potential toxicity of drugs blocking GSK1120212 is well tolerated with no dose-limiting this pathway. The ocular toxicity observed with toxicity reported so far [98]. Dose escalation is ongoing. PD0325901 and AZD6244 suggests the existence of Two other phase I/II studies of GSK1120212 have been mechanism-based adverse effects. Interestingly, new recently initiated in subjects with relapsed or refractory MEK1/2 inhibitors such as GDC-0973 and RDEA119 leukemias, and in combination with everolimus in have reduced activity in the brain, which may increase patients with solid tumors. their therapeutic window. What are the most rationale and best combination therapies with MEK1/2 inhibitors? OTHER MEK1/2 INHIBITORS The multigenetic nature of advanced cancers suggests Five other MEK1/2 inhibitors are currently being evalu- that MEK1/2 inhibitors will likely find their therapeutic ated in phase I clinical trials in advanced cancer utility in combination with other targeted agents or con- patients. These are AZD8330 (Array BioPharma/Astra- ventional cytotoxic drugs. Pre-clinical studies have Zeneca), RO5126766 and RO4987655 (Hoffmann La shown that PI3K pathway activation, through PIK3CA Roche), TAK-733 (Millenium Pharmaceuticals) and activating mutations or PTEN loss of function, signifi- AS703026 (EMD Serono). Other novel MEK1/2 inhibi- cantly decreases the response of KRAS mutant cancer tors such as RO4927350 and RO5068760 have recently cells to MEK1/2 inhibitors [102]. Importantly, simulta- been reported but have not yet passed the pre-clinical neous inhibition of the ERK1/2 and PI3K pathways was stage [99,100]. found to exert a marked synergistic effect on tumor regression [102,103]. These observations have provided a Concluding remarks and challenges strong rationale for the combination of MEK1/2 and Despite strong rationale for the clinical development of PI3K inhibitors in cancers that harbor concurrent activat- drugs targeting the ERK1/2 MAP kinase pathway in can- ing mutations in these signaling pathways. In that con- cer, the effectiveness of this approach in cancer therapy text, Merck and AstraZeneca have recently announced remains to be validated. The first and only inhibitor of the their plan to collaborate in testing a combination therapy ERK1/2 pathway that has received regulatory approval for of AZD6244 and the Akt inhibitor MK-2206 in cancer the treatment of advanced renal cell carcinoma and hepa- [104]. Finally, is the acquisition of resistance mutations in tocellular carcinoma is the Raf inhibitor sorafenib (Nexa- MEK1/MEK2 going to limit the clinical utility of these var) [101]. However, sorafenib is a multikinase inhibitor small molecule inhibitors? A recent study has reported that also inhibits the vascular endothelial growth factor the identification of a resistant MEK1 mutation in a and platelet-derived growth factor receptor tyrosine metastatic tumor that emerged in a melanoma patient kinases, as well as Flt-3 and c-Kit receptors. To what treated with AZD6244 [105]. Therefore, it may prove extent the inhibition of Raf signaling contributes to the necessary to target other components of the ERK1/2 clinical activity of the drug is not clear. Future clinical pathway in patients who develop resistance or, even- trials of more selective Raf inhibitors will help determine tually, to combine MEK1/2 inhibitors with Raf inhibitors Frémin and Meloche Journal of Hematology & Oncology 2010, 3:8 Page 9 of 11 http://www.jhoonline.org/content/3/1/8 cells and induce the formation of metastatic tumors. BMC Cancer 2008, to slow down the emergence of resistance. A phase I/II 8:337. study of RDEA119 in combination with the multikinase 16. Scholl FA, Dumesic PA, Barragan DI, Charron J, Khavari PA: Mek1/2 gene Raf inhibitor sorafenib is currently ongoing. dosage determines tissue response to oncogenic Ras signaling in the skin. Oncogene 2009, 28:1485-1495. 17. Mody N, Leitch J, Armstrong C, Dixon J, Cohen P: Effects of MAP kinase cascade inhibitors on the MKK5/ERK5 pathway. FEBS Lett 2001, 502:21-24. Acknowledgements 18. Kamakura S, Moriguchi T, Nishida E: Activation of the protein kinase ERK5/ C. Frémin is recipient of a fellowship from the Cole Foundation. S. Meloche BMK1 by receptor tyrosine kinases. Identification and characterization of holds the Canada Research Chair in Cellular Signaling. Work in the author’s a signaling pathway to the nucleus. J Biol Chem 1999, 274:26563-26571. laboratory was supported by grants from the National Cancer Institute of 19. Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, Yan C, Canada, the Cancer Research Society and the Canadian Institutes for Health McConnell P, Spessard C, Banotai C, et al: Structures of human MAP Research. kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 2004, 11:1192-1197. Authors’ contributions 20. Meloche S, Pouyssegur J: The ERK1/2 mitogen-activated protein kinase Both authors participated in drafting and editing the manuscript. Both pathway as a master regulator of the G1- to S-phase transition. authors read and approved the final manuscript. Oncogene 2007, 26:3227-3239. 21. Meloche S, Seuwen K, Pages G, Pouyssegur J: Biphasic and synergistic Competing interests activation of p44mapk (ERK1) by growth factors: correlation between The authors declare that they have no competing interests. late phase activation and mitogenicity. Mol Endocrinol 1992, 6:845-854. 22. Jones SM, Kazlauskas A: Growth-factor-dependent mitogenesis requires Received: 16 December 2009 two distinct phases of signalling. Nat Cell Biol 2001, 3:165-172. Accepted: 11 February 2010 Published: 11 February 2010 23. Yamamoto T, Ebisuya M, Ashida F, Okamoto K, Yonehara S, Nishida E: Continuous ERK activation downregulates antiproliferative genes References throughout G1 phase to allow cell-cycle progression. 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Johnston S: XL518, a potent, selective orally bioavailable MEK1 inhibitor, • Convenient online submission down-regulates the Ras/Raf/MEK/ERK pathway in vivo, resulting in tumor growth inhibition and regression in preclinical models. 19th AACR- • Thorough peer review NCI-EORTC International Conference on Molecular Targets and Cancer • No space constraints or color figure charges Therapeutics 2007, Abstract C209. • Immediate publication on acceptance 96. Rosen LS, Galatin P, Fehling JM, Laux I, Dinolfo M, Frye J, Laird D, Sikic BI: A phase 1 dose-escalation study of XL518, a potent MEK inhibitor • Inclusion in PubMed, CAS, Scopus and Google Scholar administered orally daily to subjects with solid tumors. J Clin Oncol • Research which is freely available for redistribution (abstract) 2008, 26:14585. Submit your manuscript at www.biomedcentral.com/submit

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