Merino, D, Whittle, J.R., Vaillant, F., Serrano, A., Gong, J.N., Maragno, A.L., Chanrion, M., Schneider, E., Pal, B., Giner, G., Li, X., Dewson, G., Gräsel, J., Lalaoui, N., Segal, D., Herold, M.J., Huang, D., Smyth, G.K., Geneste, O., Lessene, G., 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