期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 9, 期 401, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aam7049
关键词
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资金
- National Health and Medical Research Council, Australia (NHMRC) [1016701, 1040978, 1054618, 1086727, 1101378]
- NHMRC Independent Research Institute Infrastructure Support Scheme
- Victorian State Government through Victorian Cancer Agency funding [TRP13041]
- Operational Infrastructure Support
- Australian Cancer Research Foundation
- National Breast Cancer Foundation (NBCF) [NT-13-06]
- Servier
- Qualtrough Cancer Research Fund
- Joan Marshall Breast Cancer Research Fund
- NBCF Early Career Fellowship
- NHMRC [1101378, 1100807, 1037230, 1102742, 1043149, 1078730]
- NHMRC/NCBF Research Fellowship
- Royal Australasian College of Physicians
- Victorian Cancer Agency Early Career Seed grant [13-035]
- Worldwide Cancer Research grant [15-0042]
- National Breast Cancer Foundation [DS-15-01, NT-13-06, ECF-13-06] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1101378, 1100807, 1086727] Funding Source: NHMRC
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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