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

Merino, D; Whittle, JR; Vaillant, F; Serrano, A; Gong, JN; Giner, G; Maragno, AL; Chanrion, M; Schneider, E; Pal, B; Li, X; Dewson, G; Grasel, J; Liu, K; Lalaoui, N; Segal, D; Herold, MJ; Huang, DCS; Smyth, GK; Geneste, O; Lessene, G; Visvader, JE; Lindeman, GJ

Author(s): Merino, D; Whittle, JR; Vaillant, F; Serrano, A; Gong, JN; Giner, G; Maragno, AL; Chanrion, M; Schneider, E; Pal, B; Li, X; Dewson, G; Grasel, J; Liu, K; Lalaoui, N; Segal, D; Herold, MJ; Huang, DCS; Smyth, GK; Geneste, O; Lessene, G; Visvader, JE; Lindeman, GJ;
Details: Publication Year 2017-08-02,Volume 9,Issue #401,Page eaam7049
Journal Title: Science Translational Medicine
Publication Type: Journal Article
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 (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.
Publisher: AAAS
Research Division(s): Chemical Biology; Bioinformatics; Cell Signalling And Cell Death; Stem Cells And Cancer; Cancer And Haematology; Molecular Genetics Of Cancer
PubMed ID: 28768804
Publisher's Version: https://doi.org/10.1126/scitranslmed.aam7049
NHMRC Grants: NHMRC/1016701, NHMRC/1040978, NHMRC/1054618, NHMRC/1086727, NHMRC/1101378, NHMRC/1101378, NHMRC/1100807, NHMRC/1102742, NHMRC/1043149, NHMRC/1078730,
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Merino D et al_Science Translational Medicine 2017.pdf - (5.09MB, application/pdf)

Creation Date: 2017-08-30 02:22:32

Last Modified: 2018-08-30 08:10:42