Journal article

Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer

Delphine Merino, James R Whittle, Francois Vaillant, Antonin Serrano, Jia-Nan Gong, Goknur Giner, Ana Leticia Maragno, Maia Chanrion, Emilie Schneider, Bhupinder Pal, Xiang Li, Grant Dewson, Julius Grasel, Kevin Liu, Najoua Lalaoui, David Segal, Marco J Herold, David CS Huang, Gordon K Smyth, Olivier Geneste Show all

SCIENCE TRANSLATIONAL MEDICINE | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2017

Abstract

The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer. Using S63845-resistant cells combined with CRISPR (clu..

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Grants

Awarded by National Health and Medical Research Council, Australia (NHMRC)


Awarded by Victorian State Government through Victorian Cancer Agency funding


Awarded by National Breast Cancer Foundation (NBCF)


Awarded by NHMRC


Awarded by Victorian Cancer Agency Early Career Seed grant


Awarded by Worldwide Cancer Research grant


Awarded by National Breast Cancer Foundation


Funding Acknowledgements

This work was supported by the National Health and Medical Research Council, Australia (NHMRC) (grants 1016701, 1040978, 1054618, 1086727, and 1101378); NHMRC Independent Research Institute Infrastructure Support Scheme; the Victorian State Government through Victorian Cancer Agency funding (TRP13041) and Operational Infrastructure Support; the Australian Cancer Research Foundation; the National Breast Cancer Foundation (NBCF) (NT-13-06); Servier; the Qualtrough Cancer Research Fund; and the Joan Marshall Breast Cancer Research Fund. D.M. was supported by an NBCF Early Career Fellowship and NHMRC Project grant (1101378); J.R.W. by an NHMRC/NCBF Research Fellowship and the Royal Australasian College of Physicians; B.P. by a Victorian Cancer Agency Early Career Seed grant (13-035) and NHMRC Project Grant (1100807); N.L. by a Worldwide Cancer Research grant (15-0042); J.E.V. by an NHMRC Australia Fellowship (1037230) and Research Fellowship (1102742); and D.C.S.H. and G.J.L. by NHMRC Research Fellowships (1043149 and 1078730, respectively).