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Combining Ibrutinib with Chk1 Inhibitors Synergistically Targets Mantle Cell Lymphoma Cell Lines

Combining Ibrutinib with Chk1 Inhibitors Synergistically Targets Mantle Cell Lymphoma Cell Lines Background Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton’s tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment. Objective To overcome ibrutinib resistance, new therapeutic approaches are needed. As checkpoint kinase 1 (Chk1) inhibitors have recently been shown to be effective as single agents in MCL, we assessed the combination of ibrutinib with Chk1 inhibitors. Methods We examined the activity of ibrutinib combined with the Chk1 inhibitor PF-00477736 in eight MCL cell lines and analyzed underlying cellular and molecular effects. Results The combination was synergistic in all tested cell lines through different mechanisms. The treatment induced apoptosis in ibrutinib-sensitive cell lines, while in ibrutinib-resistant cells the effect was mainly cytostatic and occurred at micromolar concentrations of ibrutinib. Conclusions The pharmacological approach of simultaneously targeting cell cycle checkpoints (by Chk1 inhibitors) and pro- survival http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Targeted Oncology Springer Journals

Combining Ibrutinib with Chk1 Inhibitors Synergistically Targets Mantle Cell Lymphoma Cell Lines

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References (31)

Publisher
Springer Journals
Copyright
Copyright © 2018 by Springer International Publishing AG, part of Springer Nature
Subject
Medicine & Public Health; Oncology; Biomedicine, general
ISSN
1776-2596
eISSN
1776-260X
DOI
10.1007/s11523-018-0553-6
Publisher site
See Article on Publisher Site

Abstract

Background Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton’s tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment. Objective To overcome ibrutinib resistance, new therapeutic approaches are needed. As checkpoint kinase 1 (Chk1) inhibitors have recently been shown to be effective as single agents in MCL, we assessed the combination of ibrutinib with Chk1 inhibitors. Methods We examined the activity of ibrutinib combined with the Chk1 inhibitor PF-00477736 in eight MCL cell lines and analyzed underlying cellular and molecular effects. Results The combination was synergistic in all tested cell lines through different mechanisms. The treatment induced apoptosis in ibrutinib-sensitive cell lines, while in ibrutinib-resistant cells the effect was mainly cytostatic and occurred at micromolar concentrations of ibrutinib. Conclusions The pharmacological approach of simultaneously targeting cell cycle checkpoints (by Chk1 inhibitors) and pro- survival

Journal

Targeted Oncology – Springer Journals

Published: Feb 13, 2018

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