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Ref Type Journal Article
PMID (25422890)
Authors Wada M, Horinaka M, Yamazaki T, Katoh N, Sakai T
Title The dual RAF/MEK inhibitor CH5126766/RO5126766 may be a potential therapy for RAS-mutated tumor cells.
URL
Abstract Text Although melanoma is the most aggressive skin cancer, recent advances in BRAF and/or MEK inhibitors against BRAF-mutated melanoma have improved survival rates. Despite these advances, a treatment strategy targeting NRAS-mutated melanoma has not yet been elucidated. We discovered CH5126766/RO5126766 as a potent and selective dual RAF/MEK inhibitor currently under early clinical trials. We examined the activity of CH5126766/RO5126766 in a panel of malignant tumor cell lines including melanoma with a BRAF or NRAS mutation. Eight cell lines including melanoma were assessed for their sensitivity to the BRAF, MEK, or RAF/MEK inhibitor using in vitro growth assays. CH5126766/RO5126766 induced G1 cell cycle arrest in two melanoma cell lines with the BRAF V600E or NRAS mutation. In these cells, the G1 cell cycle arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27 and down-regulation of cyclinD1. CH5126766/RO5126766 was more effective at reducing colony formation than a MEK inhibitor in NRAS- or KRAS-mutated cells. In the RAS-mutated cells, CH5126766/RO5126766 suppressed the MEK reactivation caused by a MEK inhibitor. In addition, CH5126766/RO5126766 suppressed the tumor growth in SK-MEL-2 xenograft model. The present study indicates that CH5126766/RO5126766 is an attractive RAF/MEK inhibitor in RAS-mutated malignant tumor cells including melanoma.

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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
BRAF V600E melanoma sensitive RO5126766 Preclinical - Cell culture Actionable In a preclinical study, RO5126766 (VS-6766) treatment induced cell cycle arrest, decreased Mek and Erk phosphorylation, and inhibited growth of melanoma cells harboring BRAF V600E in culture (PMID: 25422890). 25422890
NRAS Q61R melanoma sensitive RO5126766 Preclinical - Cell line xenograft Actionable In a preclinical study, RO5126766 (VS-6766) treatment induced cell cycle arrest, decreased Mek and Erk phosphorylation, and inhibited growth of melanoma cells harboring NRAS Q61R in culture, and inhibited tumor growth in cell line xenograft models (PMID: 25422890). 25422890
BRAF V600E melanoma conflicting PD-0325901 Preclinical - Cell line xenograft Actionable In a preclinical study, PD-0325901 treatment induced cell cycle arrest and inhibited growth of melanoma cells harboring BRAF V600E in culture (PMID: 25422890). 25422890
NRAS Q61R melanoma sensitive PD-0325901 Preclinical - Cell culture Actionable In a preclinical study, PD-0325901 treatment induced cell cycle arrest and inhibited growth of melanoma cells harboring NRAS Q61R in culture (PMID: 25422890). 25422890