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

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.

Long‐term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib

“…We provided the first evidence of the correlation of acquired TP53 and NSD2 gene mutations in progression and/or blastoid transformation in MCL on ibrutinib. Although our mutation results are from a small sample size and require further validation in large patient cohort, we believe that our data significantly add to the previous reports on ibrutinib resistance in MCL showing the role of the tumour microenvironment (Jayappa et al , ; Zhao et al , ), MAP3K14 alterations (Rahal et al , ) and mutations in chromatin modifier genes, such as NSD2 (Meissner et al , ), in MCL progression. One of the limitations of the mutation data reported in our study is due to the lack of matched germline samples for all samples, therefore the copy number data has a noisy background, especially the LOH calling, and therefore we focused on the deep deletions and high copy number gains, which had a high signal/noise ratio.…”

“…The mechanisms of ibrutinib resistance and the relevance of clonal evolution are being studied in B cell lymphoid malignancies (Burger et al , ; Jayappa et al , ; Landau et al , ; Zhao et al , ; Hershkovitz‐Rokah et al , ). In contrast to SLL/CLL, where the primary mode of ibrutinib resistance is considered to be via BTK C481S and PLCG2 gene mutations (Ahn et al , ; Woyach et al , ), studies in MCL (Chiron et al , ; Martin et al , ) and in follicular lymphoma (FL) (Jain et al , ) indicate that these mutations were uncommon in ibrutinib‐resistant patients.…”

Clinical and functional impact of recurrent S1PR1 mutations in mantle cell lymphoma

“…12 However, ;40% of MCL patients develop resistance to ibrutinib, and adhesion of MCL cells to the stroma contributes to this resistance. 25 Patrussi et al reported that ibrutinib elevates expression of S1PR1 (simultaneously decreasing CCR7) in chronic lymphocytic leukemia. 26 However, further studies are needed to determine if S1PR1 mutations impact the outcome of ibrutinib therapy in MCL.…”

Differential B-cell receptor signaling requirement for adhesion of mantle cell lymphoma cells to stromal cells

“…9,10 Interactions between MCL cells and their microenvironment are mediated by a complex network of cell adhesion molecules and cell surface signaling molecules as well as cytokines and their receptors. [11][12][13] Cells in the MCL microenvironment secrete cytokines, chemokines, and other soluble molecules that are important for tumor cell trafficking, homing, survival and drug resistance. For example, stromal cells in secondary lymphatic tissues constitutively secrete chemokines, like CXCL12, that facilitate homing and survival of tumor cells expressing its main receptor, CXCR4.…”

“…[22][23][24] The BCR is implicated in the pathogenesis of MCL where microenvironment-induced BCR activation enhances MCL survival and drug resistance. 12,25 Ibrutinib, previously called PCI-32765, is a clinicaly approved drug that covalently binds to BTK, inhibiting its kinase activity irreversibly. 26,27 Ibrutinib has been granted breakthrough therapy designation for the treatment of patients with MCL and chronic lymphocytic leukemia (CLL).…”