Molecularly-targeted agents have improved outcomes for a subset of patients with BRAF-mutated melanoma, but treatment of resistant and BRAF wild-type tumors remains a challenge. The MERTK receptor tyrosine kinase is aberrantly expressed in melanoma and can contribute to oncogenic phenotypes. Here we report the effect of treatment with a MERTK-selective small molecule inhibitor, UNC2025, in preclinical models of melanoma. In melanoma cell lines, treatment with UNC2025 potently inhibited phosphorylation of MERTK and downstream signaling, induced cell death, and decreased colony formation. In patient-derived melanoma xenograft models, treatment with UNC2025 blocked or significantly reduced tumor growth. Importantly, UNC2025 had similar biochemical and functional effects in both BRAF-mutated and BRAF wild-type models and irrespective of NRAS mutational status, implicating MERTK inhibition as a potential therapeutic strategy in tumors that are not amenable to BRAF-targeting and for which there are limited treatment options. In BRAF-mutated cell lines, combined treatment with UNC2025 and the BRAF inhibitor vemurafenib provided effective inhibition of oncogenic signaling through ERK, AKT, and STAT6, increased induction of cell death, and decreased colony-forming potential. Similarly, in NRAS-mutated cell lines, addition of UNC2025 to cobimetinib therapy increased cell death and decreased colony-forming potential. In a BRAF-mutated patient-derived xenograft, treatment with combined UNC2025 and vemurafenib was well-tolerated and significantly decreased tumor growth compared with vemurafenib alone. These data support the use of UNC2025 for treatment of melanoma, irrespective of BRAF or NRAS mutational status, and suggest a role for MERTK and targeted combination therapy in BRAF and NRAS-mutated melanoma.
Bibliographical noteFunding Information:
Research Fund and Federal Funds from the National Cancer Institute, National Institute of Health, under Contract No. HHSN261200800001E.
The authors wish to thank Christine Childs and the University of Colorado Cancer Center Flow Cytometry Core Facility (NIH P30CA046934) for expert technical assistance, the University of Colorado Diabetes and Endocrinology Research Center Molecular Biology Core Facility (NIH P30DK57516) for cell line authentication services, the Children's Healthcare of Atlanta and Emory University Pediatric Flow Cytometry Core for use of core facilities, and Eleana Vasileaidi for technical assistance. This work was supported by a sponsored research agreement with Merck Inc. to D.K. Graham, grant support from the Melanoma Research Alliance (Saban Family Foundation-MRA Team Science Award to R. Kami, T. Burstyn-Cohen, S.G. Earnhardt, S.V. Frye, H.S. Earp, and D.K. Graham), and a generous contribution from Dr. Bill Robinson (University of Colorado). K.A. Minson is supported by the Atlanta Pediatric Scholars Program sponsored by the NIH National Institute of Child Health and Human Development Child Health Research Career Development Award (K12HD072245). Medicinal chemistry efforts (X. Wang and S.V. Frye) were supported by the University Cancer
© 2018 American Association for Cancer Research.