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

Xiaohong Zhao, Tint Lwin, Ariosto Silva, Bijal Shah, Jiangchuan Tao, Bin Fang, Liang Zhang, Kai Fu, Chengfeng Bi, Jiannong Li, Huijuan Jiang, Mark B. Meads, Timothy Jacobson, Maria Silva, Allison Distler, Lancia Darville, Ling Zhang, Ying Han, Dmitri Rebatchouk, Maurizio Di Liberto, Lynn C. Moscinski, John M. Koomen, William S. Dalton, Kenneth H. Shain, Michael Wang, Eduardo Sotomayor and Jianguo Tao ()
Additional contact information
Xiaohong Zhao: Moffitt Cancer Center
Tint Lwin: Moffitt Cancer Center
Ariosto Silva: Department of Cancer Imaging and Metabolism
Bijal Shah: Moffitt Cancer Center
Jiangchuan Tao: Moffitt Cancer Center
Bin Fang: Proteomics Core Facility, Moffitt Cancer Center
Liang Zhang: University of Texas MD Anderson Cancer Center
Kai Fu: University of Nebraska Medical Center
Chengfeng Bi: University of Nebraska Medical Center
Jiannong Li: Biostatistics Core Facility, Moffitt Cancer Center
Huijuan Jiang: Tianjin Medical University General Hospital
Mark B. Meads: Moffitt Cancer Center
Timothy Jacobson: Department of Cancer Imaging and Metabolism
Maria Silva: Department of Cancer Imaging and Metabolism
Allison Distler: Moffitt Cancer Center
Lancia Darville: Proteomics Core Facility, Moffitt Cancer Center
Ling Zhang: Moffitt Cancer Center
Ying Han: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory
Dmitri Rebatchouk: nPharmakon LLC
Maurizio Di Liberto: Weill Cornell Medicine
Lynn C. Moscinski: Moffitt Cancer Center
John M. Koomen: Moffitt Cancer Center
William S. Dalton: Moffitt Cancer Center
Kenneth H. Shain: Moffitt Cancer Center
Michael Wang: University of Texas MD Anderson Cancer Center
Eduardo Sotomayor: George Washington University
Jianguo Tao: Moffitt Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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 evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling. Combinatorial disruption of B-cell receptor signalling and PI3K-AKT-mTOR axis leads to release of MCL cells from TME, reversal of drug resistance and enhanced anti-MCL activity in MCL patient samples and patient-derived xenograft models. This study unifies TME-mediated de novo and acquired drug resistance mechanisms and provides a novel combination therapeutic strategy against MCL and other B-cell malignancies.

Date: 2017
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DOI: 10.1038/ncomms14920

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