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Dynamic molecular monitoring reveals that SWI/SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma [RNA-Seq]

ABSTRACT: Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and non-responders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI/SNF chromatin remodeling complex were present in all patients with primary resistance and 2/3 patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored providing concurrent information on treatment response and tumour evolution. Functional modeling demonstrated that compromise of the SWI/SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a paradigm for real-time assessment of innovative targeted therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122509 | GEO | 2018/11/21

REPOSITORIES: GEO

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Dynamic molecular monitoring reveals that SWI/SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma [ATAC-Seq]

Project description:Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and non-responders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI/SNF chromatin remodeling complex were present in all patients with primary resistance and 2/3 patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored providing concurrent information on treatment response and tumour evolution. Functional modeling demonstrated that compromise of the SWI/SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a paradigm for real-time assessment of innovative targeted therapies.

2018-11-21 | GSE122510 | GEO

Homo sapiens

Project description:Dynamic molecular monitoring reveals that SWI/SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma

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Integrative multi-omic analysis of the SWI/SNF complex defines a new clinical subgroup of lung adenocarcinoma patients

Project description:Mammalian SWI/SNF complexes are ATP-dependent chromatin remodelers composed of varying combinations of subunits that, together, fine-tune transcriptional regulation and genome integrity. SWI/SNF complex subunits have been identified as major targets of mutations in several tumor types suggesting a relevant role in tumorigenesis. However, there is a lack of comprehensive studies of the whole SWI/SNF complex in lung adenocarcinoma (LUAD). Here, we combined genomic, transcriptomic, and proteomic approaches to identify which SWI/SNF subunits are present in lung cells, as well as their mutational status, mRNA levels, and protein levels in LUAD. For these purposes, we combined data from LUAD primary tumors, normal lung and LUAD cell lines, and external LUAD data from The Cancer Genome Atlas. Importantly, we found that mutations in the SWI/SNF complex in LUAD not only present a high incidence but we also observed that only the mutational status of the SWI/SNF complex and not the mutations in any of the top ten LUAD driver genes is associated with poorer overall survival in LUAD patients. Furthermore, we showed that the expression of the SWI/SNF complex in LUAD suffers an overall repression that cannot be explained exclusively by genetic alterations. Based on our findings, we propose that SWI/SNF-mutant LUAD tumors should be considered as a distinct subgroup with practical applications in the prognosis and follow-up of LUAD patients.

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