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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-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.

SUBMITTER: Yuan X

PROVIDER: S-EPMC7400788 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Yuan Xi X Tang Zhiyu Z Du Rong R Yao Zhan Z Cheung Shing-Hu SH Zhang Xinwen X Wei Jing J Zhao Yuan Y Du Yunguang Y Liu Ye Y Hu Xiaoxia X Gong Wenfeng W Liu Yong Y Gao Yajuan Y Huang Zhiyue Z Cao Zongfu Z Wei Min M Zhou Changyou C Wang Lai L Rosen Neal N Smith Paul D PD Luo Lusong L

Molecular oncology 20200518 8

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 lif ...[more]

PMID: 32336014

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Project description:Mitogen-activated protein kinase (MAPK) pathway dysregulation is implicated in >30% of all cancers, rationalizing the development of RAF, MEK and ERK inhibitors. While BRAF and MEK inhibitors improve BRAF mutant melanoma patient outcomes, these inhibitors had limited success in other MAPK dysregulated tumors, with insufficient pathway suppression and likely pathway reactivation. In this study we show that inhibition of either MEK or ERK alone only transiently inhibits the MAPK pathway due to feedback reactivation. Simultaneous targeting of both MEK and ERK nodes results in deeper and more durable suppression of MAPK signaling that is not achievable with any dose of single agent, in tumors where feedback reactivation occurs. Strikingly, combined MEK and ERK inhibition is synergistic in RAS mutant models but only additive in BRAF mutant models where the RAF complex is dissociated from RAS and thus feedback productivity is disabled. We discovered that pathway reactivation in RAS mutant models occurs at the level of CRAF with combination treatment resulting in a markedly more active pool of CRAF. However, distinct from single node targeting, combining MEK and ERK inhibitor treatment effectively blocks the downstream signaling as assessed by transcriptional signatures and phospho-p90RSK. Importantly, these data reveal that MAPK pathway inhibitors whose activity is attenuated due to feedback reactivation can be rescued with sufficient inhibition by using a combination of MEK and ERK inhibitors. The MEK and ERK combination significantly suppresses MAPK pathway output and tumor growth in vivo to a greater extent than the maximum tolerated doses of single agents, and results in improved anti-tumor activity in multiple xenografts as well as in two Kras mutant genetically engineered mouse (GEM) models. Collectively, these data demonstrate that combined MEK and ERK inhibition is functionally unique, yielding greater than additive anti-tumor effects and elucidates a highly effective combination strategy in MAPK-dependent cancer, such as KRAS mutant tumors.

Dataset Information

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

Publications

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

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