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. 2019 Jan;25(1):119-129.
doi: 10.1038/s41591-018-0243-z. Epub 2018 Nov 19.

Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma

Rishu Agarwal #  1   2 , Yih-Chih Chan #  1   2 , Constantine S Tam  3   4   5 , Tane Hunter  1   2 , Dane Vassiliadis  1   2 , Charis E Teh  6   7 , Rachel Thijssen  6   7 , Paul Yeh  1   2   3 , Stephen Q Wong  1 , Sarah Ftouni  1 , Enid Y N Lam  1   2 , Mary Ann Anderson  3   6   7 , Christiane Pott  8 , Omer Gilan  1   2 , Charles C Bell  1   2 , Kathy Knezevic  1 , Piers Blombery  1   3 , Kathleen Rayeroux  9 , Adrian Zordan  9 , Jason Li  1   2 , David C S Huang  6   7 , Meaghan Wall  5   9   10 , John F Seymour  2   3 , Daniel H D Gray  6   7 , Andrew W Roberts  3   6   7   11 , Mark A Dawson  12   13   14   15 , Sarah-Jane Dawson  16   17   18
Affiliations

Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma

Rishu Agarwal et al. Nat Med. 2019 Jan.

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.

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