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 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2020 -- Source: Scopus |
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