Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer
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
WEHI 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
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2017-08-30 02:22:32
Last Modified: 2018-08-30 08:10:42
An error has occurred. This application may no longer respond until reloaded. Reload 🗙