Dataset Information

ABPP of Ibrutinib Resistance in B Cell Malignancies

ABSTRACT: Ibrutinib,a novel Bruton'styrosine kinase inhibitor, demonstrated high response rates in B-cell lymphomas but a growing number of ibrutinib treated patients relapse with resistance, fulminant progression and accelerated mortality. Using chemical proteomics and a high-throughput ex vivo assay in a reconstructed tumor microenvironment (TME), we determined the molecular basis for ibrutinib activity and mechanism of acquired ibrutinib resistance. Reciprocal activation of PI3K-AKT-mTOR and integrin β1 signaling were identified as a signaling hub of kinome for ibrutinib resistance, resulting in enforced TME-lymphoma interactions, promoting mantle cell lymphoma (MCL) growth and drug resistance. Combinatorial disruption of BCR signaling and ibrutinib resistance associated pathways led to release of MCL cells from TME, reversal of drugresistance and enhanced anti-MCL activity in murine and patient-derived xenograft models. This study integrated TME-mediated de-novo and acquired drug resistance mechanisms and provides the rationale for novel combination therapeutic strategy against MCL and other B cell malignancies.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Culture

DISEASE(S): B-cell Lymphoma

SUBMITTER: John Koomen

LAB HEAD: Jianguo Tao, MD/PhD

PROVIDER: PXD005734 | Pride | 2018-10-26

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 336

Publications

Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma.

Zhao Xiaohong X Lwin Tint T Silva Ariosto A Shah Bijal B Tao Jiangchuan J Fang Bin B Zhang Liang L Fu Kai K Bi Chengfeng C Li Jiannong J Jiang Huijuan H Meads Mark B MB Jacobson Timothy T Silva Maria M Distler Allison A Darville Lancia L Zhang Ling L Han Ying Y Rebatchouk Dmitri D Di Liberto Maurizio M Moscinski Lynn C LC Koomen John M JM Dalton William S WS Shain Kenneth H KH Wang Michael M Sotomayor Eduardo E Tao Jianguo J

Nature communications 20170418

The novel Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutio ...[more]

PMID: 28416797

Similar Datasets

Project description:Drug-tolerant “persister” tumor cells underlie the emergence of drug-resistant clones contribute to relapse and disease progression; thus, identifying actionable targets that disable persisters and mitigate relapse are a high priority need. Although the BCL2-targeting agent venetoclax (ABT-199) has shown promising responses in mantle cell and double hit B cell lymphomas, resistance often arises, yet mechanistically how this occurs is unclear. Here we report that ABT-199 resistance can evolve from persister clones that have selective deletions at 18q21 that involve the drug target BCL2 and the apoptotic regulators Noxa (PMAIP1) and TCF4. Notably, reprogramming of super enhancers (SE) in persisters contributes to resistance, where there is a selection for SE-directed overexpression of the apoptotic regulator BCL2A1 and oncogenic transcription factors IKZF1 and FOXC1. At the same time, the SE reprogramming confers an opportunity for overcoming ABT-199 resistance. An unbiased drug screen on a platform that recapitulates the lymphoma microenvironment revealed that persisters are vulnerable to inhibitors of transcription initiation and elongation, and especially so to inhibitors of cyclin-dependent kinase 7 (CDK7) that is essential for transcription initiation. Specifically, CDK7 loss or inhibition eliminated the persister phenotype by disabling SE-driven expression of BCL2A1, IKZF1 and FOXC1. Thus, the co-treatment of ABT-199 with CDK7 inhibitors blocked the evolution of drug resistance, and provoked tumor regression in models of mantle cell lymphoma (MCL) and double hit lymphomas (DHL) that overexpress both MYC and BCL2. Together, these findings establish loss of apoptotic regulators and an adaptive transcriptional response as drug resistance mechanisms in lymphoma, more importantly, establish a rationale for transcription inhibition-based combination strategies to prevent and overcome drug resistance in B cell malignancies toward BCL2 inhibitor.

			Action	DRS
	F003692.dat	Other
	F003693.dat	Other
	F003694.dat	Other
	F003695.dat	Other
	F003696.dat	Other