Proteomics

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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  

TISSUE(S): Cell Culture

DISEASE(S): B-cell Lymphoma

SUBMITTER: John Koomen  

LAB HEAD: Jianguo Tao, MD/PhD

PROVIDER: PXD005734 | Pride | 2018-10-26

REPOSITORIES: pride

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Publications


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]

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