Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma
| Autor: | Kathleen C. Rayeroux, Jason Li, Omer Gilan, Sarah Ftouni, Daniel H.D. Gray, Kathy Knezevic, Constantine S. Tam, Sarah-Jane Dawson, Meaghan Wall, Adrian Zordan, Mark A. Dawson, Charis E Teh, Rachel Thijssen, Tane Hunter, Stephen Q. Wong, Yih-Chih Chan, Mary Ann Anderson, David C.S. Huang, Christiane Pott, Charles C. Bell, Dane Vassiliadis, Piers Blombery, Enid Y.N. Lam, John F. Seymour, Rishu Agarwal, Andrew W. Roberts, Paul Yeh |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mutation Venetoclax business.industry General Medicine medicine.disease medicine.disease_cause Somatic evolution in cancer Minimal residual disease General Biochemistry Genetics and Molecular Biology SWI/SNF Lymphoma 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry 030220 oncology & carcinogenesis Ibrutinib medicine Cancer research Mantle cell lymphoma business |
| Zdroj: | Nature Medicine. 25:119-129 |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | 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 nonresponders. 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 two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor 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 model for real-time assessment of innovative targeted therapies. |
| Databáze: | OpenAIRE |
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