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|Ref Type||Journal Article|
|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.|
|Date||2018 Mar 15|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|RAF709||RAF-709||BRAF Inhibitor 21 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|
|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|
|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|
|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 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|
|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|