Inhibition of MERTK Promotes Suppression of Tumor Growth in BRAF Mutant and BRAF Wild-Type Melanoma

• Type of Material: Article
• Authors: Lenka Sinik, University of Colorado; Katherine Minson, Emory University; John J Tentler, University of Colorado, Aurora; Jacqueline Carrico, University of Colorado, Aurora; Stacey M Bagby, University of Colorado, Aurora; William A Robinson, University of Colorado, Aurora; Rotem Kami, Hebrew University of Jerusalem; Tal Burstyn-Cohen, Hebrew University of Jerusalem; Gail S Eckhardt, University of Texas Austin; Xiaodong Wang, University of North Carolina Chapel Hill; Stephen Frye, University of North Carolina Chapel Hill; Shelton H Earp, UNC Lineberger Comprehensive Cancer Center; Deborah DeRyckere, Emory University; Douglas Graham, Emory University
• Language: English
• Date: 2019-02-01
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019, American Association for Cancer Research
• Final Published Version (URL): http://dx.doi.org/10.1158/1535-7163.MCT-18-0456
• Title of Journal or Parent Work: MOLECULAR CANCER THERAPEUTICS
• Volume: 18
• Issue: 2
• Start Page: 278
• End Page: 288
• Grant/Funding Information: 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 Research Fund and Federal Funds from the National Cancer Institute, National Institute of Health, under Contract No. HHSN261200800001E.
• Keywords: EXPRESSION; REGULATOR; RESISTANCE; AXL; Life Sciences & Biomedicine; Science & Technology; SURVIVIN; MULTICENTER; Oncology; CELLS; ONCOGENE; RECEPTOR TYROSINE KINASES; MUTATIONS

Abstract

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.