title: Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not BRAF-mutant melanoma.
abstract: Effective targeted therapy strategies are still lacking for the 15-20% of melanoma patients whose melanomas are driven by oncogenic NRAS. Here, we report on the NRAS-specific behavior of amuvatinib, a kinase inhibitor with activity against c-KIT, Axl, PDGFRα, and Rad51. An analysis of BRAF-mutant and NRAS-mutant melanoma cell lines showed the NRAS-mutant cohort to be enriched for targets of amuvatinib, including Axl, c-KIT, and the Axl ligand Gas6. Increasing concentrations of amuvatinib selectively inhibited the growth of NRAS-mutant, but not BRAF-mutant melanoma cell lines, an effect associated with induction of S-phase and G2/M-phase cell cycle arrest and induction of apoptosis. Mechanistically, amuvatinib was noted to either inhibit Axl, AKT, and MAPK signaling or Axl and AKT signaling and to induce a DNA damage response. In three-dimensional cell culture experiments, amuvatinib was cytotoxic against NRAS-mutant melanoma cell lines. Thus, we show for the first time that amuvatinib has proapoptotic activity against melanoma cell lines, with selectivity observed for those harboring oncogenic NRAS.
authors.affiliation: Departments of aMolecular Oncology bExperimental Therapeutics cCutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Inna V
authors.initials: IV
authors.lastname: Fedorenko
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.forename: John M
authors.initials: JM
authors.lastname: Koomen
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Gibney
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
mesh_terms: D017209:Apoptosis; D018929:Cell Culture Techniques; D002453:Cell Cycle; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004249:DNA Damage; D011905:Genes, ras; D006801:Humans; D020128:Inhibitory Concentration 50; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008024:Ligands; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D010879:Piperazines; D040901:Proteomics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D013890:Thiourea; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D019009:Proto-Oncogene Proteins c-kit; D011743:Pyrimidines; D020794:Receptor Protein-Tyrosine Kinases; D013890:Thiourea; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C482119:BRAF protein, human; C521047:amuvatinib; C000722289:AXL protein, human