RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K-RAS mutant tumors

Mol Oncol. 2020 Aug;14(8):1833-1849. doi: 10.1002/1878-0261.12698. Epub 2020 May 18.


The mutation of K-RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K-RAS mutations. The reduced sensitivity of K-RAS-mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C-RAF and with the reactivation of mitogen-activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors lifirafenib (BGB-283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD-0325901) and selumetinib, in suppressing the proliferation of K-RAS-mutated non-small-cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B-RAFV600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF-dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K-RAS-mutated cells. This synergistic effect was also observed in several K-RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho-ERK blockade in enhancing the antitumor activity observed in the K-RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K-RAS-mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K-RAS mutations and other MAPK pathway aberrations.

Keywords: MEK inhibitor; RAF dimer inhibitor; RAS-mutated cancer; combination therapy; synergy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation / genetics*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Multimerization* / drug effects
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Time Factors
  • Up-Regulation / drug effects
  • Vemurafenib / pharmacology
  • Xenograft Model Antitumor Assays


  • AZD 6244
  • Antineoplastic Agents
  • Benzimidazoles
  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Vemurafenib
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)