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Ibrutinib resistance mantle cell lymphoma [Pt_RNA]

ABSTRACT: Ibrutinib, a bruton's tyrosine kinase inhibitor, was shown to have high response rates in mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. However, emergence of ibrutinib resistance (IR) and subsequent fatal progression is of significant clinical concern. By implementing genomics, chemical proteomics and drug screening, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the malignant phenotype of IR. Accordingly, IR MCL cells are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 9 (CDK9). Thus, targeting transcriptional activation offers a novel strategy to prevent the emergence of IR and overcome IR via impeding IR-associated cellular signaling reprogramming in MCL. In addition, our ex-vivo microfluidic image-based functional drug screen can function not only as new technology platforms for predicting clinical therapeutic response but also, in conjunction with genomic profiling in primary MCL samples, identify the molecular vulnerabilities for drug resistance evolution, providing insight into the underlying IR mechanisms for MCL and other B-cell malignancies

ORGANISM(S): Homo sapiens

PROVIDER: GSE141335 | GEO | 2021/04/26

REPOSITORIES: GEO

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ibrutinib resistance mantle cell lymphoma [ChIP-seq]

Project description:Ibrutinib, a bruton's tyrosine kinase inhibitor, was shown to have high response rates in mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. However, emergence of ibrutinib resistance (IR) and subsequent fatal progression is of significant clinical concern. By implementing genomics, chemical proteomics and drug screening, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the malignant phenotype of IR. Accordingly, IR MCL cells are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 9 (CDK9). Thus, targeting transcriptional activation offers a novel strategy to prevent the emergence of IR and overcome IR via impeding IR-associated cellular signaling reprogramming in MCL. In addition, our ex-vivo microfluidic image-based functional drug screen can function not only as new technology platforms for predicting clinical therapeutic response but also, in conjunction with genomic profiling in primary MCL samples, identify the molecular vulnerabilities for drug resistance evolution, providing insight into the underlying IR mechanisms for MCL and other B-cell malignancies

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Activity of the novel BTK inhibitor TG-1701 is associated with the disruption of the Ikaros signaling pathway in responder B-NHL patients and with sensitization to anti-CD20 therapy in B-NHL xenografts

Project description:Covalent Bruton's tyrosine kinase inhibitors (BTKis) have transformed the treatment of B-cell non-Hodgkin lymphoma (B-NHL), including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but their activity has been limited by off-target toxicity and acquired drug resistance. TG-1701 is a novel irreversible and highly specific BTKi being presently under study in a phase 1 clinical trial in patients with relapsed/refractory B-NHL alone and in combination with ublituximab, a CD20 antibody, and umbralisib, a dual PI3Kδ and CK1ε inhibitor. Here we show, for the first time that phosphoproteomic analysis of CLL patients receiving a BTKi (TG-1701) led to a non-supervised clustering that matched the clinical outcomes and separated a group of “responders” from a group of “non-responders”. This clustering was based on a selected list of 96 phosphosites, with Ikaros-Ser442/445 phosphorylation as a potential marker for TG-1701 efficacy. RNA-seq analysis followed by qPCR and western blot validation further revealed that TG-1701 treatment blunted the Ikaros gene signature only in responder patients, as well as in BTKi-sensitive, but not BTKi-insensitive, B-NHL cell lines and xenografts. Importantly, and in contrast with ibrutinib, TG-1701 did not impair FcγR-driven antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) triggered by the anti-CD20 antibodies rituximab and ublituximab in a multicellular MCL co-culture system. In addition, TG-1701 cooperated with ublituximab coupled to umbralisib (also referred as the U2 regimen) in reducing the tumor growth in both ibrutinib-sensitive and ibrutinib-insensitive mouse models of MCL. Altogether, these data validate phosphoproteomic as a broken thread to omics analysis in the clinic and support the use of TG-1701-U2 combination in R/R B-NHL patients, irrespective of prior response to ibrutinib.

2021-09-22 | PXD023231 | Pride

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Project description:The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease. Cancer Res; 77(24); 7038-48. ©2017 AACR.

2018-04-03 | GSE98206 | GEO

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