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

Merino, D and Whittle, J.R. and Vaillant, F. and Serrano, A. and Gong, J.N. and Maragno, A.L. and Chanrion, M. and Schneider, E. and Pal, B. and Giner, G. and Li, X. and Dewson, G. and Gräsel, J. and Lalaoui, N. and Segal, D. and Herold, M.J. and Huang, D. and Smyth, G.K. and Geneste, O. and Lessene, G. and Visvader, J.E. and Lindeman, J.L. (2017) Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer. Science Translational Medicine, 9 (401). ISSN 19466242

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 andwith trastuzumab or lapatinib inHER2-amplified breast cancer. Using S63845-resistant cells combinedwith CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated 9) technology, we identified deletion of BAK and up-regulation of prosurvival proteins as potential mechanisms that confer resistance to S63845 in breast cancer. Collectively, our findings provide a strong rationale for the clinical evaluation of MCL-1 inhibitors in breast cancer.

Item Type: Article
Date Deposited: 17 Jan 2018 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/32387

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