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| 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. | ||||||||||||
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| 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. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
|---|
| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|---|---|---|---|
| GDC0879 | GDC-0879|GDC 0879 | BRAF Inhibitor 26 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 |
|---|---|---|---|---|---|---|---|
| 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 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 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 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 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 | 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 |
| 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 | 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 |