RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors. Issue 8 (18th May 2020)

• Record Type: Journal Article
• Authors: Yuan, Xi; Tang, Zhiyu; Du, Rong; Yao, Zhan; Cheung, Shing‐Hu; Zhang, Xinwen; Wei, Jing; Zhao, Yuan; Du, Yunguang; Liu, Ye; Hu, Xiaoxia; Gong, Wenfeng; Liu, Yong; Gao, Yajuan; Huang, Zhiyue; Cao, Zongfu; Wei, Min; Zhou, Changyou; Wang, Lai; Rosen, Neal; Smith, Paul D.; Luo, Lusong
• Is Part Of: Molecular oncology. Volume 14:Issue 8(2020)
• Page Start: 1833
• Page End: 1849
• Publication Date: 2020-05-18
• Subjects: combination therapy -- MEK inhibitor -- RAF dimer inhibitor -- RAS‐mutated cancer -- synergy; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12698
• Languages: English
• ISSNs: 1574-7891

Abstract

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‐RAF V600E 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. Abstract : The reduced sensitivity of K‐RAS‐mutated cancer cells to MEK inhibitors (MEKi), such as selumetinib and mirdametinib, is associated with feedback phosphorylation of MEK by upstream RAF reactivation. RAF dimer inhibitors, such as lifirafenib and compound C, in combination with MEKi potently suppress RAF‐dependent MEK phosphorylation and lead to sustained inhibition of MAPK signaling and tumor growth.