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

Nat Commun. 2017 Apr 18;8:14920. doi: 10.1038/ncomms14920.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Lymphoma, Mantle-Cell / drug therapy*
  • Lymphoma, Mantle-Cell / pathology
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mechanistic Target of Rapamycin Complex 2 / metabolism
  • Mice
  • Protein Kinases / metabolism
  • Proteome / metabolism
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use*
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use*
  • Receptors, Antigen, B-Cell / metabolism
  • Signal Transduction / drug effects
  • Tumor Microenvironment / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • PCI 32765
  • Proteome
  • Pyrazoles
  • Pyrimidines
  • Receptors, Antigen, B-Cell
  • Protein Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2