Ibrutinib, a bruton’s tyrosine kinase (BTK) inhibitor, provokes robust clinical responses in aggressive mantle cell lymphoma (MCL), yet many patients relapse with lethal Ibrutinib-resistant (IR) disease. Here, using genomic, chemical proteomic, and drug screen profiling, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the aggressive phenotypes of IR. Accordingly, IR MCL cells are vulnerable to inhibitors of the transcriptional machinery and especially so to inhibitors of cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the positive transcription elongation factor b (P-TEFb) of RNA polymerase II (RNAPII). Further, CDK9 inhibition disables reprogrammed signaling circuits and prevents the emergence of IR in MCL. Finally, and importantly, we find that a robust and facile ex vivo image-based functional drug screening platform can predict clinical therapeutic responses of IR MCL and identify vulnerabilities that can be targeted to disable the evolution of IR.Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
About The Expert
Xiaohong Zhao
Michelle Y Wang
Huijuan Jiang
Tint Lwin
Paul M Park
Jing Gao
Mark B Meads
Yuan Ren
Tao Li
Jiao Sun
Naima Ahmed Fahmi
Satishkumar Singh
Lalit Sehgal
Xuefeng Wang
Ariosto S Silva
Eduardo M Sotomayor
Kenneth H Shain
John L Cleveland
Michael Wang
Wei Zhang
Jun Qi
Bijal D Shah
Jianguo Tao
References
PubMed