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 Cancer research
Vol 69
Issue 7
Date 2009 Apr 01
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 22 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
GDC0879 GDC-0879 BRAF Inhibitor 19 CRAF Inhibitor 11 GDC0879 is a selective small molecular inhibitor of BRAF and CRAF (RAF1), which inhibits survival of tumor cells (PMID: 19276360).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
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 inhibitor in cell culture (PMID: 19276360), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Mar 2019). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 BFAF V600E and PTEN loss in cell culture (PMID: 19276360). 19276360
KRAS mutant non-small cell lung carcinoma resistant GDC0879 Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cells harboring KRAS mutations were resistant to GDC0879 induced growth inhibition in culture (PMID: 19276360). 19276360
KRAS mutant colon cancer resistant GDC0879 Preclinical - Cell culture Actionable In a preclinical study, colon cancer cells harboring KRAS mutations 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 wild-type KRAS G12D pancreatic cancer resistant GDC0879 Preclinical - Cell line xenograft Actionable In a preclinical study, GDC0879 failed to inhibit growth of BRAF wild-type pancreatic cancer cells harboring KRAS G12D in cell line xenograft 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 L485Y non-small cell lung 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 wild-type KRAS G12C non-small cell lung carcinoma resistant GDC0879 Preclinical - Pdx Actionable In a preclinical study, GDC0879 failed to inhibit growth of BRAF wild-type non-small cell lung cancer cells harboring KRAS G12C in patient-derived xenograft models (PMID: 19276360). 19276360
BRAF wild-type KRAS G13D colon cancer resistant GDC0879 Preclinical - Cell line xenograft Actionable In a preclinical study, GDC0879 failed to inhibit growth of BRAF wild-type colon cancer cells harboring KRAS G13D in culture ann in cell line xenograft models (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 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 wild-type KRAS G12V non-small cell lung carcinoma resistant GDC0879 Preclinical - Pdx Actionable In a preclinical study, GDC0879 failed to inhibit growth of BRAF wild-type non-small cell lung cancer cells harboring KRAS G12V in patient-derived xenograft models (PMID: 19276360). 19276360
BRAF wild-type non-small cell lung 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
BRAF wild-type KRAS Q61K non-small cell lung carcinoma resistant GDC0879 Preclinical - Cell line xenograft Actionable In a preclinical study, GDC0879 failed to inhibit growth of BRAF wild-type non-small cell lung cancer cells harboring KRAS Q61K in culture and in cell line xenograft models (PMID: 19276360). 19276360