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|Ref Type||Journal Article|
|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|
|Date||2017 Aug 02|
|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.|
|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|
|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||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|
|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|