| Literature DB >> 30455436 |
Rishu Agarwal1,2, Yih-Chih Chan1,2, Constantine S Tam3,4,5, Tane Hunter1,2, Dane Vassiliadis1,2, Charis E Teh6,7, Rachel Thijssen6,7, Paul Yeh1,2,3, Stephen Q Wong1, Sarah Ftouni1, Enid Y N Lam1,2, Mary Ann Anderson3,6,7, Christiane Pott8, Omer Gilan1,2, Charles C Bell1,2, Kathy Knezevic1, Piers Blombery1,3, Kathleen Rayeroux9, Adrian Zordan9, Jason Li1,2, David C S Huang6,7, Meaghan Wall5,9,10, John F Seymour2,3, Daniel H D Gray6,7, Andrew W Roberts3,6,7,11, Mark A Dawson12,13,14,15, Sarah-Jane Dawson16,17,18.
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 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.Entities:
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Year: 2018 PMID： 30455436 DOI： 10.1038/s41591-018-0243-z
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440