LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors.

Autor:	Monaco KA; Bristol Myers-Squibb, Cambridge, Massachusetts., Delach S; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Yuan J; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Mishina Y; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Fordjour P; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Labrot E; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., McKay D; Ventus Therapeutics, Montreal, Quebec, Canada., Guo R; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Higgins S; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Wang HQ; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Liang J; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Bui K; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Green J; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Aspesi P; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Ambrose J; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Mapa F; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Griner L; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Jaskelioff M; Skyhawk Therapeutics, Waltham, Massachusetts., Fuller J; Novartis Institutes for Biomedical Research, Emeryville, California., Crawford K; AbSci, Vancouver, Washington., Pardee G; Novartis Institutes for Biomedical Research, Emeryville, California., Widger S; Novartis Institutes for Biomedical Research, Emeryville, California., Hammerman PS; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Engelman JA; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Stuart DD; Scorpion Therapeutics, Boston, Massachusetts., Cooke VG; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts., Caponigro G; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. giordano.caponigro@novartis.com.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Apr 01; Vol. 27 (7), pp. 2061-2073. Date of Electronic Publication: 2020 Dec 22.
DOI:	10.1158/1078-0432.CCR-20-2563
Abstrakt:	Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: LXH254 is a novel RAF inhibitor, which is able to inhibit dimerized BRAF and CRAF, as well as monomeric BRAF, while largely sparing ARAF. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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