Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer Academic Article uri icon


  • 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.


  • Merino, Delphine
  • 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, Marco
  • Huang, DCS
  • Smyth, GK
  • Geneste, O
  • Lessene, G
  • Visvader, JE
  • Lindeman, GJ

publication date

  • 2017

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