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|Ref Type||Journal Article|
|Authors||Monaco KA, Delach S, Yuan J, Mishina Y, Fordjour P, Labrot E, McKay D, Guo R, Higgins S, Wang HQ, Liang J, Bui K, Green J, Aspesi P, Ambrose J, Mapa F, Griner L, Jaskelioff M, Fuller J, Crawford K, Pardee G, Widger S, Hammerman PS, Engelman JA, Stuart DD, Cooke VG, Caponigro G|
|Title||LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2021 Apr 01|
|Abstract Text||Targeting RAF for antitumor therapy in RAS-mutant tumors holds promise. Herein, we describe in detail novel properties of the type II RAF inhibitor, LXH254.LXH254 was profiled in biochemical, in vitro, and in vivo assays, including examining the activities of the drug in a large panel of cancer-derived cell lines and a comprehensive set of in vivo models. In addition, activity of LXH254 was assessed in cells where different sets of RAF paralogs were ablated, or that expressed kinase-impaired and dimer-deficient variants of ARAF.We describe an unexpected paralog selectivity of LXH254, which is able to potently inhibit BRAF and CRAF, but has less activity against ARAF. LXH254 was active in models harboring BRAF alterations, including atypical BRAF alterations coexpressed with mutant K/NRAS, and NRAS mutants, but had only modest activity in KRAS mutants. In RAS-mutant lines, loss of ARAF, but not BRAF or CRAF, sensitized cells to LXH254. ARAF-mediated resistance to LXH254 required both kinase function and dimerization. Higher concentrations of LXH254 were required to inhibit signaling in RAS-mutant cells expressing only ARAF relative to BRAF or CRAF. Moreover, specifically in cells expressing only ARAF, LXH254 caused paradoxical activation of MAPK signaling in a manner similar to dabrafenib. Finally, in vivo, LXH254 drove complete regressions of isogenic variants of RAS-mutant cells lacking ARAF expression, while parental lines were only modestly sensitive.LXH254 is a novel RAF inhibitor, which is able to inhibit dimerized BRAF and CRAF, as well as monomeric BRAF, while largely sparing ARAF.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|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 loss NRAS Q61K||melanoma||decreased response||LXH 254||Preclinical - Cell culture||Actionable||In a preclinical study, CRISPR-Cas9 mediated knockout of BRAF in a melanoma cell line harboring NRAS Q61K led to decreased sensitivity to LXH254 treatment compared to parental cells harboring BRAF D287H and NRAS Q61K in culture (PMID: 33355204).||33355204|
|BRAF D287H NRAS Q61K||melanoma||predicted - sensitive||LXH 254||Preclinical - Cell line xenograft||Actionable||In a preclinical study, a melanoma cell line harboring BRAF D287H and NRAS Q61K was sensitive to treatment with LXH254, demonstrating inhibition of cell proliferation in culture, and inhibition of tumor growth in a cell line xenograft model of melanoma (PMID: 33355204).||33355204|
|BRAF V600E||melanoma||predicted - sensitive||LXH 254||Preclinical - Cell line xenograft||Actionable||In a preclinical study, a melanoma cell line harboring BRAF V600E was sensitive to treatment with LXH254, demonstrating inhibition of cell proliferation in culture, and inhibition of tumor growth and tumor regression in a cell line xenograft model of melanoma (PMID: 33355204).||33355204|