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

Authors: Yuan, X.; Tang, Z.; Du, R.; Yao, Z.; Cheung, S. H.; Zhang, X.; Wei, J.; Zhao, Y.; Du, Y.; Liu, Y.; Hu, X.; Gong, W.; Liu, Y.; Gao, Y.; Huang, Z.; Cao, Z.; Wei, M.; Zhou, C.; Wang, L.; Rosen, N.; Smith, P. D.; Luo, L.
Article Title: RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K-RAS mutant tumors
Abstract: 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. ©2020 BeiGene. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Keywords: combination therapy; synergy; mek inhibitor; raf dimer inhibitor; ras-mutated cancer
Journal Title: Molecular Oncology
Volume: 14
Issue: 8
ISSN: 1878-0261
Publisher: FEBS Press  
Date Published: 2020-08-01
Start Page: 1833
End Page: 1849
Language: English
DOI: 10.1002/1878-0261.12698
PUBMED: 32336014
PROVIDER: scopus
PMCID: PMC7400788
Notes: Article -- Export Date: 1 September 2020 -- Source: Scopus
Citation Impact
MSK Authors
  1. Neal Rosen
    398 Rosen
  2. Zhan Yao
    37 Yao