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Ref Type Journal Article
PMID (28768804)
Authors Merino D, Whittle JR, Vaillant F, Serrano A, Gong JN, Giner G, Maragno AL, Chanrion M, Schneider E, Pal B, Li X, Dewson G, Gräsel J, Liu K, Lalaoui N, Segal D, Herold MJ, Huang DCS, Smyth GK, Geneste O, Lessene G, Visvader JE, Lindeman GJ
Title Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer.
Journal Science translational medicine
Vol 9
Issue 401
Date 2017 Aug 02
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 amp Her2-receptor positive breast cancer sensitive Lapatinib + S63845 Preclinical - Cell culture Actionable In a preclinical study, the combination of Tykerb (lapatinib) and S63845 demonstrated synergy in an ERBB2 (HER2)-amplified breast cancer cell line in culture, resulting in decreased cell viability (PMID: 28768804). 28768804
ERBB2 amp Her2-receptor positive breast cancer sensitive S63845 + Trastuzumab Preclinical - Pdx & cell culture Actionable In a preclinical study, S63845 and Herceptin (trastuzumab) demonstrated synergy in ERBB2 (HER2)-amplified breast cancer cells in culture and in ERBB2 (HER2)-amplified breast cancer patient-derived xenograft (PDX) models, resulting in enhanced tumor growth inhibition and overall survival compared to either agent alone (PMID: 28768804). 28768804
Unknown unknown triple-receptor negative breast cancer not applicable Docetaxel + S63845 Preclinical - Pdx Actionable In a preclinical study, S63845 and Taxotere (docetaxel) demonstrated synergy in triple-negative breast cancer patient-derived xenograft models, resulting in enhanced tumor growth inhibition and overall survival compared to either agent alone (PMID: 28768804). 28768804
Unknown unknown triple-receptor negative breast cancer not applicable S63845 Preclinical - Cell culture Actionable In a preclinical study, S63845 decreased viability of triple negative breast cancer (TNBC) cell lines and TNBC patient-derived xenograft (PDX) tumor cells in culture (PMID: 28768804). 28768804
Unknown unknown Her2-receptor positive breast cancer not applicable S63845 Preclinical - Cell culture Actionable In a preclinical study, S63845 decreased viability of an ERBB2 (HER2)-amplified breast cancer cell line and ERBB2 (HER2)-amplified patient-derived xenograft (PDX) tumor cells in culture (PMID: 28768804). 28768804