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

被引：176

作者：

Agarwal, Rishu ^{[1
,2
]}

Chan, Yih-Chih ^{[1
,2
]}

Tam, Constantine S. ^{[1
,3
,4
,5
]}

Hunter, Tane ^{[1
,2
]}

Vassiliadis, Dane ^{[1
,2
]}

Teh, Charis E. ^{[6
,7
]}

Thijssen, Rachel ^{[6
,7
]}

Yeh, Paul ^{[1
,2
,3
]}

Wong, Stephen Q. ^{[1
]}

Ftouni, Sarah ^{[1
]}

Lam, Enid Y. N. ^{[1
,2
]}

Anderson, Mary Ann ^{[1
,3
,6
,7
]}

Pott, Christiane ^{[8
]}

Gilan, Omer ^{[1
,2
]}

Bell, Charles C. ^{[1
,2
]}

Knezevic, Kathy ^{[1
]}

Blombery, Piers ^{[1
,3
]}

Rayeroux, Kathleen ^{[9
]}

Zordan, Adrian ^{[9
]}

Li, Jason ^{[1
,2
]}

Huang, David C. S. ^{[6
,7
]}

Wall, Meaghan ^{[5
,9
,10
]}

Seymour, John F. ^{[1
,2
,3
]}

Gray, Daniel H. D. ^{[6
,7
]}

Roberts, Andrew W. ^{[1
,3
,6
,7
,11
]}

Dawson, Mark A. ^{[1
,2
,3
,11
]}

Dawson, Sarah-Jane ^{[1
,2
,11
]}

机构：

[1] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[2] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia

[3] Royal Melbourne Hosp, Dept Haematol, Melbourne, Vic, Australia

[4] St Vincents Hosp, Dept Haematol, Melbourne, Vic, Australia

[5] St Vincents Hosp, Dept Med, Melbourne, Vic, Australia

[6] Walter & Eliza Hall Inst Med Res, Melbourne, Vic, Australia

[7] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia

[8] Univ Hosp Schleswig Holstein, Kiel, Germany

[9] Victorian Canc Cytogenet Serv, Melbourne, Vic, Australia

[10] St Vincents Inst Med Res, Melbourne, Vic, Australia

[11] Univ Melbourne, Ctr Canc Res, Melbourne, Vic, Australia

来源：

NATURE MEDICINE | 2019年 / 25卷 / 01期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

MINIMAL RESIDUAL DISEASE; BRUTONS TYROSINE KINASE; CIRCULATING TUMOR DNA; GENE-EXPRESSION; PROGNOSTIC INFORMATION; CLONAL EVOLUTION; INHIBITOR; CANCER; BTK; ACTIVATION;

D O I：

10.1038/s41591-018-0243-z

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：119 / +

页数：14

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