Reference Detail

Ref Type Journal Article
PMID (29343524)
Authors Shao W, Mishina YM, Feng Y, Caponigro G, Cooke VG, Rivera S, Wang Y, Shen F, Korn JM, Mathews Griner LA, Nishiguchi G, Rico A, Tellew J, Haling JR, Aversa R, Polyakov V, Zang R, Hekmat-Nejad M, Amiri P, Singh M, Keen N, Dillon MP, Lees E, Ramurthy S, Sellers WR, Stuart DD
Title Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAF.
Journal Cancer research
Vol 78
Issue 6
Date 2018 Mar 15
URL
Abstract Text Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here, we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared with cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in in vivo tumor models harboring KRAS mutation. Furthermore, RAF709 elicited regression of primary human tumor-derived xenograft models with BRAF, NRAS, or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next-generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS-mutant tumors.Significance: In an effort to develop RAF inhibitors with the appropriate pharmacological properties to treat RAS mutant tumors, RAF709, a compound with potency, selectivity, and in vivo properties, was developed that will allow preclinical therapeutic hypothesis testing, but also provide an excellent probe to further unravel the complexities of RAF kinase signaling. Cancer Res; 78(6); 1537-48. ©2018 AACR.

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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
RAF709 RAF709 8 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
RAF709 BRAF Inhibitor 19 CRAF Inhibitor 11 RAF709 is an ATP-competitive inhibitor that inhibits both BRAF monomers and RAF dimers, resulting in growth inhibition in tumor cells (PMID: 29343524).
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
NRAS Q61K melanoma predicted - sensitive RAF709 Preclinical - Cell culture Actionable In a preclinical study, RAF709 inhibited Erk signaling in melanoma cells harboring NRAS Q61K in culture (PMID: 29343524). 29343524
NRAS Q61K lung cancer sensitive RAF709 Preclinical - Cell line xenograft Actionable In a preclinical study, RAF709 inhibited Erk signaling and proliferation of lung cancer cells harboring NRAS Q61K in culture, and resulted in tumor regression in cell line xenograft models (PMID: 29343524). 29343524
NRAS act mut lung non-small cell carcinoma sensitive RAF709 Preclinical - Pdx Actionable In a preclinical study, RAF709 inhibited tumor growth in patient-derived xenograft (PDX) models of non-small cell lung cancer harboring NRAS activating mutations (PMID: 29343524). 29343524
NRAS mutant Advanced Solid Tumor sensitive RAF709 Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines harboring NRAS mutations demonstrated increased sensitivity to RAF709 compared to NRAS wild-type cells in culture (PMID: 29343524). 29343524
NRAS Q61L melanoma sensitive RAF709 Preclinical - Cell culture Actionable In a preclinical study, RAF709 inhibited Erk signaling and proliferation of melanoma cells harboring NRAS Q61L in culture (PMID: 29343524). 29343524
BRAF act mut lung non-small cell carcinoma sensitive RAF709 Preclinical - Pdx Actionable In a preclinical study, RAF709 inhibited tumor growth in patient-derived xenograft (PDX) models of non-small cell lung cancer harboring BRAF activating mutations (PMID: 29343524). 29343524
BRAF mutant Advanced Solid Tumor sensitive RAF709 Phase I Actionable In a preclinical study, cancer cell lines harboring BRAF mutations demonstrated increased sensitivity to RAF709 compared to BRAF wild-type cells in culture (PMID: 29343524). 29343524
BRAF V600E melanoma sensitive RAF709 Preclinical - Cell culture Actionable In a preclinical study, RAF709 inhibited Erk signaling and proliferation of melanoma cells harboring BRAF V600E in culture (PMID: 29343524). 29343524