Reference Detail

Ref Type

Journal Article

PMID

(19276360)

Authors

Hoeflich KP, Herter S, Tien J, Wong L, Berry L, Chan J, O'Brien C, Modrusan Z, Seshagiri S, Lackner M, Stern H, Choo E, Murray L, Friedman LS, Belvin M

Title

Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	69	7	2009 Apr 01	3042-51	Cancer Res

URL

Abstract Text

Oncogenic activation of the BRAF serine/threonine kinase has been associated with initiation and maintenance of melanoma tumors. As such, development of pharmacologic agents to target RAF proteins or their effector kinases is an area of intense investigation. Here we report the biological properties of GDC-0879, a highly selective, potent, and orally bioavailable RAF small-molecule inhibitor. We used extracellular signal-regulated kinase (ERK)-1/2 and mitogen-activated protein kinase/ERK kinase (MEK)-1/2 phosphorylation as biomarkers to explore the relationship between tumor outcome and pharmacodynamic inhibition of the RAF-MEK-ERK pathway. In GDC-0879-treated mice, both cell line- and patient-derived BRAF(V600E) tumors exhibited stronger and more sustained pharmacodynamic inhibition (>90% for 8 hours) and improved survival compared with mutant KRAS-expressing tumors. Despite the involvement of activated RAF signaling in RAS-induced tumorigenesis, decreased time to progression was observed for some KRAS-mutant tumors following GDC-0879 administration. Moreover, striking differences were noted for RAF and MEK inhibition across a panel of 130 tumor cell lines. Whereas GDC-0879-mediated efficacy was associated strictly with BRAF(V600E) status, MEK inhibition also attenuated proliferation and tumor growth of cell lines expressing wild-type BRAF (81% KRAS mutant, 38% KRAS wild type). The responsiveness of BRAF(V600E) melanoma cells to GDC-0879 could be dramatically altered by pharmacologic and genetic modulation of phosphatidylinositol 3-kinase pathway activity. These data suggest that GDC-0879-induced signaling changes are dependent on the point of oncogenic activation within the RAS network. Taken together, these studies increase our understanding of the molecular determinants for antitumor efficacy resulting from RAF pathway inhibition and have implications for therapeutic intervention in the clinic.

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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
GDC0879	GDC0879	21	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
GDC0879		GDC-0879\|GDC 0879	BRAF Inhibitor 25 CRAF Inhibitor 12	GDC0879 is a selective small molecular inhibitor of BRAF and CRAF (RAF1), which inhibits survival of tumor cells (PMID: 19276360, PMID: 29249695).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	L485Y	missense	unknown	BRAF L485Y lies within the protein kinase domain of the Braf protein (UniProt.org). L485Y has been demonstrated to confer resistance to Raf inhibition in cell culture (PMID: 19276360), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Aug 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF L485Y	lung non-small cell carcinoma	resistant	GDC0879	Preclinical - Cell culture	Actionable	In a preclinical study, non-small cell lung cancer cells harboring BRAF L485Y were resistant to GDC0879 induced growth inhibition in culture (PMID: 19276360).	19276360
BRAF N581Y	colon cancer	resistant	GDC0879	Preclinical - Cell culture	Actionable	In a preclinical study, colon cancer cells harboring BRAF N581Y were resistant to GDC0879 induced growth inhibition in culture (PMID: 19276360).	19276360
BRAF wild-type NRAS Q61K	melanoma	resistant	GDC0879	Preclinical - Pdx	Actionable	In a preclinical study, GDC0879 failed to inhibit growth of BRAF wild-type melanoma cells harboring NRAS Q61K in patient-derived xenograft models (PMID: 19276360).	19276360
BRAF V600E	melanoma	sensitive	GDC0879	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, GDC0879 inhibited survival of melanoma cell lines harboring BRAF V600E in cell culture, cell line xenograft and patient-derived xenograft (PDX) models (PMID: 19276360).	19276360
BRAF V600E	colon cancer	sensitive	GDC0879	Preclinical - Cell line xenograft	Actionable	In a preclinical study, GDC0879 inhibited survival of colon cancer cell lines harboring BRAF V600E in cell culture and cell line xenograft models (PMID: 19276360).	19276360
BRAF wild-type	melanoma	resistant	GDC0879	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, GDC0879 failed to inhibit growth of BRAF wild-type melanoma cells in cell culture, cell line xenograft models, and patient-derived xenograft models (PMID: 19276360).	19276360
NRAS mutant	colon cancer	resistant	GDC0879	Preclinical - Cell culture	Actionable	In a preclinical study, colon cancer cells harboring NRAS mutations were resistant to GDC0879 induced growth inhibition in culture (PMID: 19276360).	19276360
BRAF V600E PTEN loss	melanoma	sensitive	GDC0879 + Pictilisib	Preclinical - Cell culture	Actionable	In a preclinical study, GDC0879 and Pictilisib (GDC-0941) synergistically inhibited survival of melanoma cell lines harboring BRAF V600E and PTEN loss in cell culture (PMID: 19276360).	19276360
BRAF wild-type	lung non-small cell carcinoma	resistant	GDC0879	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, GDC0879 failed to inhibit growth of BRAF wild-type non-small cell lung cancer cells in culture and in patient-derived xenograft models (PMID: 19276360).	19276360