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BET bromodomain inhibitors synergize with ATR inhibitors in melanoma in melanoma.

Journal article
Authors Somsundar Veppil Muralidharan
Berglind Osk Einarsdottir
Joydeep Bhadury
Mattias F Lindberg
Jin Wu
Eric Campeau
Roger Olofsson Bagge
Ulrika Stierner
Lars Ny
Lisa M Nilsson
Jonas A Nilsson
Published in Cell Death & Disease
Volume 8
Issue 8
Pages 1-7
ISSN 2041-4889
Publication year 2017
Published at Institute of Clinical Sciences, Department of Oncology
Pages 1-7
Language en
Links dx.doi.org/10.1038/cddis.2017.383
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Cancer and Oncology

Abstract

Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.

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