Transcriptional programming drives Ibrutinib-resistance evolution in mantle cell lymphoma.
Cell Rep, 2021/03/16;34(11):108870.
Zhao X[1], Wang MY[1], Jiang H[1], Lwin T[1], Park PM[2], Gao J[1], Meads MB[3], Ren Y[1], Li T[1], Sun J[4], Fahmi NA[4], Singh S[5], Sehgal L[5], Wang X[6], Silva AS[7], Sotomayor EM[8], Shain KH[3], Cleveland JL[9], Wang M[10], Zhang W[4], Qi J[2], Shah BD[11], Tao J[12]
Affiliations
PMID: 33730585DOI: 10.1016/j.celrep.2021.108870
Impact factor: 9.995
Abstract
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.
Keywords: BRD4; CDK9; Ibrutinib; combination therapy; enhancer; kinome; mantle cell lymphoma; resistance; transcriptome
MeSH terms
Adenine; Animals; Cell Cycle Proteins; Cell Line, Tumor; Cyclin-Dependent Kinase 9; Drug Resistance, Neoplasm; Enhancer Elements, Genetic; Humans; Lymphoma, Mantle-Cell; Male; Mice, Inbred NOD; Mice, SCID; Piperidines; Protein Kinases; RNA Polymerase II; Signal Transduction; Transcription Factors; Transcription, Genetic; Transcriptome; Treatment Outcome; Mice
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