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Ref Type Journal Article
PMID (32336014)
Authors Yuan X, Tang Z, Du R, Yao Z, Cheung SH, 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 PD, Luo L
Title RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K-RAS mutant tumors.
Journal Molecular oncology
Vol 14
Issue 8
Date 2020 08
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS Q61K lung non-small cell carcinoma sensitive BGB-283 + Pimasertib Preclinical - Cell culture Actionable In a preclinical study, the combination of Lifirafenib (BGB-283) and Pimasertib (MSC1936369B) synergistically inhibited proliferation of a non-small cell lung cancer cell line harboring NRAS Q61K in culture, and demonstrated improved efficacy over either agent alone (PMID: 32336014). 32336014
NRAS Q61K lung non-small cell carcinoma sensitive BGB-283 + PD-0325901 Preclinical - Cell culture Actionable In a preclinical study, the combination of Lifirafenib (BGB-283) and PD-0325901 synergistically inhibited proliferation of a non-small cell lung cancer cell line harboring NRAS Q61K in culture, and demonstrated improved efficacy over either agent alone (PMID: 32336014). 32336014