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.
Highlights
The novel Bruton’s tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression
We investigated the role of B-cell receptor (BCR) signalling in stroma-mediated Mantle cell lymphoma (MCL) cell survival and drug resistance and used a co-culture model to evaluate the impact of stromal cells on phosphorylation status of the BCR downstream proteins CD79a, Bruton’s tyrosine kinase (BTK), ERK and AKT
When CD79a was depleted by using shRNA, stroma-induced activation of BTK and AKT was abolished (Supplementary Fig. 1a), supporting that BCR is required for stroma-induced activation of BTK, ERK and AKT
Summary
The novel Bruton’s tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. 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-b1 signalling. Ibrutinib is a novel BTK inhibitor that has shown an unprecedented overall response rate and progression-free survival in relapsed/refractory MCL patients and in patients with other B-cell disorders[10,11]. Longitudinal drug screening with ex vivo, in vivo TME, and patient-derived xenograft (PDX) models, we identified a major kinase network involving PI3K-AKT-mTOR/integrin b1-integrin-linked kinase (ILK) as a central hub for TME–lymphoma interactions mediating IR.
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