Transcriptional programming drives Ibrutinib-resistance evolution in mantle cell lymphoma.
Cell Rep
; 34(11): 108870, 2021 03 16.
Article
in En
| MEDLINE
| ID: mdl-33730585
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperidines
/
Transcription, Genetic
/
Adenine
/
Drug Resistance, Neoplasm
/
Lymphoma, Mantle-Cell
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Cell Rep
Year:
2021
Document type:
Article
Affiliation country:
United States