COMBATING NRAS MUTANT MELANOMA: FROM BENCH TO BEDSIDE.
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ABSTRACT:
SUBMITTER: Echevarria-Vargas IM
PROVIDER: S-EPMC5959291 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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, PDGFR?, 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.
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Project description:Melanoma is the deadliest form of skin cancer and the incidence continues to rise in the United States and worldwide. Activating mutations in RAS oncogenes are found in roughly a third of all human cancers. Mutations in NRAS occur in approximately a fifth of cutaneous melanomas and are associated with aggressive clinical behavior. Cells harboring oncogenic NRAS mutations exhibit activation of multiple signaling cascades, including PI3K/Akt, MEK-ERK and RAL, which collectively stimulate cancer growth. While strategies to target N-Ras itself have proven ineffective, targeting one or more N-Ras effector pathways has shown promise in preclinical models. Despite promising preclinical data, current therapies for NRAS mutant melanoma remain limited. Immune checkpoint inhibitors and targeted therapies for BRAF mutant melanoma are transforming the treatment of metastatic melanoma, but the ideal treatment for NRAS mutant melanoma remains unknown. Improved understanding of NRAS mutant melanoma and relevant N-Ras effector signaling modules will be essential to develop new treatment strategies.
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