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Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma.
Agarwal, Rishu; Chan, Yih-Chih; Tam, Constantine S; Hunter, Tane; Vassiliadis, Dane; Teh, Charis E; Thijssen, Rachel; Yeh, Paul; Wong, Stephen Q; Ftouni, Sarah; Lam, Enid Y N; Anderson, Mary Ann; Pott, Christiane; Gilan, Omer; Bell, Charles C; Knezevic, Kathy; Blombery, Piers; Rayeroux, Kathleen; Zordan, Adrian; Li, Jason; Huang, David C S; Wall, Meaghan; Seymour, John F; Gray, Daniel H D; Roberts, Andrew W; Dawson, Mark A; Dawson, Sarah-Jane.
Afiliação
  • Agarwal R; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Chan YC; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
  • Tam CS; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Hunter T; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
  • Vassiliadis D; Department of Haematology, Royal Melbourne Hospital & Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Teh CE; Department of Haematology, St. Vincent's Hospital, Melbourne, Victoria, Australia.
  • Thijssen R; Department of Medicine, St. Vincent's Hospital, Melbourne, Victoria, Australia.
  • Yeh P; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Wong SQ; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
  • Ftouni S; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Lam EYN; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
  • Anderson MA; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
  • Pott C; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
  • Gilan O; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
  • Bell CC; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
  • Knezevic K; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Blombery P; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
  • Rayeroux K; Department of Haematology, Royal Melbourne Hospital & Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Zordan A; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Li J; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Huang DCS; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Wall M; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
  • Seymour JF; Department of Haematology, Royal Melbourne Hospital & Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Gray DHD; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
  • Roberts AW; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
  • Dawson MA; University Hospital of Schleswig-Holstein, Kiel, Germany.
  • Dawson SJ; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Nat Med ; 25(1): 119-129, 2019 01.
Article em En | MEDLINE | ID: mdl-30455436
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirazóis / Pirimidinas / Sulfonamidas / Fatores de Transcrição / Proteínas Cromossômicas não Histona / Resistencia a Medicamentos Antineoplásicos / Compostos Bicíclicos Heterocíclicos com Pontes / Linfoma de Célula do Manto / Mutação Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Austrália
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirazóis / Pirimidinas / Sulfonamidas / Fatores de Transcrição / Proteínas Cromossômicas não Histona / Resistencia a Medicamentos Antineoplásicos / Compostos Bicíclicos Heterocíclicos com Pontes / Linfoma de Célula do Manto / Mutação Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Austrália