Novel RAF/MEK inhibitor CH5126766/VS-6766 has efficacy in combination with eribulin for the treatment of triple-negative breast cancer

Cancer Sci. 2021 Oct;112(10):4166-4175. doi: 10.1111/cas.15071. Epub 2021 Aug 1.


Various molecular-targeting drugs have markedly improved the treatment of patients with breast cancer. As yet, therapies for triple-negative breast cancer are mainly cytotoxic agents. To investigate the novel therapy for triple-negative breast cancer, we herein examined the effects of a new combination therapy comprising a RAF/MEK inhibitor CH5126766, also known as VS-6766, which we originally discovered, and eribulin. The combination of CH5126766 and eribulin potently inhibited cell growth in the triple-negative breast cancer cell lines tested. The underlying mechanism in the efficacy of this combination treatment in vitro and in vivo was due to enhanced apoptosis through the suppression of survivin and Bcl-2 family proteins. We also showed the suppressed expression of programmed cell death ligand 1 (PD-L1) in combination therapy in vivo. We found that combination therapy with eribulin and CH5126766 for triple-negative breast cancer inhibited cell growth by apoptosis and raised a possibility that immune responses through suppression of PD-L1 might partially contribute to inhibition of tumor growth, indicating the potential of this combination as a novel strategy for triple-negative breast cancer.

Keywords: CH5126766/VS-6766; PD-L1; TNBC; apoptosis; eribulin.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • B7-H1 Antigen / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Coumarins / therapeutic use*
  • Female
  • Furans / therapeutic use*
  • Ketones / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Oncogene Protein v-akt / metabolism
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-raf / antagonists & inhibitors*
  • Random Allocation
  • Survivin / metabolism
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / immunology
  • Triple Negative Breast Neoplasms / metabolism
  • Tumor Stem Cell Assay


  • B7-H1 Antigen
  • Coumarins
  • Furans
  • Ketones
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • RO5126766
  • Survivin
  • Oncogene Protein v-akt
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinase Kinases
  • eribulin