Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PloS one	9	11	2014	e113217	PLoS One

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	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	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
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
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