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	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	78	6	2018 Mar 15	1537-1548	Cancer Res

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	7	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
RAF709		RAF-709	BRAF Inhibitor 25 CRAF Inhibitor 12	RAF709 is an ATP-competitive inhibitor that inhibits both BRAF monomers and RAF dimers, resulting in growth inhibition in tumor cells (PMID: 29343524).

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	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
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 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 mutant	Advanced Solid Tumor	sensitive	RAF709	Preclinical - Cell culture	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
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 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
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