Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular oncology	14	8	2020 08	1833-1849	Mol Oncol

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	Lifirafenib + 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	Lifirafenib + 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