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 LibertoLynn C. Moscinski, John M. Koomen, William S. Dalton, Kenneth H. Shain, Michael Wang, Eduardo Sotomayor, Jianguo Tao

Research output: Contribution to journalArticle

48 Scopus citations

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.

Original languageEnglish (US)
Article number14920
JournalNature communications
Volume8
DOIs
StatePublished - Apr 18 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Zhao, X., Lwin, T., Silva, A., Shah, B., Tao, J., Fang, B., Zhang, L., Fu, K., Bi, C., Li, J., Jiang, H., Meads, M. B., Jacobson, T., Silva, M., DIstler, A., Darville, L., Zhang, L., Han, Y., Rebatchouk, D., ... Tao, J. (2017). Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nature communications, 8, [14920]. https://doi.org/10.1038/ncomms14920