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

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

Author information

1
Departments of Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center, Tampa, Florida 33612, USA.
2
Department of Cancer Imaging and Metabolism, Moffitt Cancer Center, Tampa, Florida 33612, USA.
3
Department of Malignant Hematology, Moffitt Cancer Center, Tampa, Florida 33612, USA.
4
Department of Laboratory Medicine and Hematopathology, Moffitt Cancer Center, Tampa, Florida 33612, USA.
5
Proteomics Core Facility, Moffitt Cancer Center, Tampa, Florida 33612, USA.
6
Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
7
Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
8
Biostatistics Core Facility, Moffitt Cancer Center, Tampa, Florida 33612, USA.
9
Department of Hematology, Tianjin Medical University General Hospital, Tianjian 300052, China.
10
Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory, Tianjing 300040, China.
11
nPharmakon LLC, Piscataway, New Jersey 08854, USA.
12
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
13
Department of Hematology &Oncology, George Washington University, Washington DC 20052, USA.

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.

PMID:
28416797
PMCID:
PMC5399304
DOI:
10.1038/ncomms14920
[Indexed for MEDLINE]
Free PMC Article

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