AI Article Synopsis
- BH3 mimetics that inhibit prosurvival proteins like MCL-1 could improve cancer treatment, especially since MCL-1 is often overactive in breast cancer, leading to worse outcomes.
- The MCL-1 inhibitor S63845 was tested in breast cancer cell lines and mice, showing promising results when combined with other drugs like docetaxel and trastuzumab, particularly in aggressive breast cancer types.
- Research into S63845-resistant cells revealed that changes like deletion of BAK and increased prosurvival proteins may cause resistance, suggesting that further clinical trials for MCL-1 inhibitors are warranted in breast cancer therapy.
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.
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| http://dx.doi.org/10.1126/scitranslmed.aam7049 | DOI Listing |
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