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Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not BRAF-mutant melanoma

Fedorenko, Inna V.a; Fang, Binb; Koomen, John M.b; Gibney, Geoffrey T.c; Smalley, Keiran S.M.a,c

doi: 10.1097/CMR.0000000000000103
ORIGINAL ARTICLES: Basic research

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.

Departments of aMolecular Oncology

bExperimental Therapeutics

cCutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

All supplementary digital content is available directly from the corresponding author.

Correspondence to Keiran S.M. Smalley, PhD, Department of Molecular Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA Tel: +1 813 745 8725; fax: +1 813 449 8260; e-mail: keiran.smalley@moffitt.org

Received May 11, 2014

Accepted May 20, 2014

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins