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

Author

Listed:
  • 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
    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
    Moffitt Cancer Center)

  • Michael Wang

    (University of Texas MD Anderson Cancer Center)

  • Eduardo Sotomayor

    (George Washington University)

  • Jianguo Tao

    (Moffitt Cancer Center
    Moffitt Cancer Center
    Moffitt Cancer Center)

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.

Suggested Citation

  • 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 , 2017. "Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14920
    DOI: 10.1038/ncomms14920
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