The Mer Receptor Tyrosine Kinase (RTK) is overexpressed in hematologic and epithelial malignancies. Mer is not a proliferative driver but rather produces a cancer cell-intrinsic survival signal. In addition, tumor-associated macrophages (TAMs) express Mer, which upon binding ligand-associated with apoptotic material, triggers engulfment (effercytosis). The Mer signal also polarizes macrophages towards an M2-like, wound healing, anti-inflammatory state, calming the innate immune response when ingesting “self”. We have previously shown that syngeneic polyoma middle T (PyVmT) breast cancer cells demonstrate markedly attenuated growth when orthotopically implanted into Mer knock-out mice, with Mer -/- TAMs of PyVmT tumors producing M1-like inflammatory cytokines (JCI 123:3231, 2013). This result suggests that Mer inhibition could enhance innate anti-tumor responses, and toward that end, we examine the activity of first-in-class, orally bioavailable MerTK inhibitor on tumor growth in autochthonous murine tumor models. UNC MerTKi is 5-fold selective for Mer vs. Axl/Tyro3 and has favorable pharmacokinetics. Once daily, oral dosing inhibits the growth of Mer-expressing leukemia and NSCLC xenografts. UNC MerTKi was assessed in immune-competent, genetically engineered murine models (GEMMs) in the UNC Lineberger Mouse Phase 1 Unit (MP1U). After dose-finding studies in wild-type mice established an MTD, the inhibitor was given at 120 mpk/d in mouse chow, a dose which did not cause weight loss and produced a measurable effect (i.e. inhibition of second phase platelet aggregation, a known Mer pharmacodynamics marker). This dose did not exhibit single agent activity in a murine model of breast cancer (C3TAg), but exhibited pronounced single agent activity in RAS-driven, INK4a/Arf null melanoma GEMM (TRIA). The MP1U has previously reported the efficacy of 15 chemotherapeutic and/or targeted regimens in a large (>220) cohort of TRIA mice (CCR 18:5290, 2012). The overall response was 10% (partial responses and stable disease). There were no complete responses. A combination of MEK (AZD 6244) and PI3K/mTOR (BEZ235) inhibitors were the most active previous regimen (responses seen in 9/18 mice = 50%, with 0 CRs) with moderate toxicity. UNC MerTKi exhibited greater activity (6/8 mice = 75%, with 3 CRs) with mild, well-tolerated toxicity in the TRIA model. TRIA cell lines do not express Mer, suggesting that UNC MerTKi as a monotherapy may induce responses via Mer inhibition in TAMs and the tumor microenvironment, or via inhibition of Axl, Tyro or an unknown target. In summary, a potent and selective Mer inhibitor exhibited greater pre-clinical efficacy in a highly faithful model of RAS-mutant melanoma than any other drug tested to date, including several compounds that are FDA approved for use in metastatic melanoma. Citation Format: H Shelton Earp, David Darr, Albert Zimmermann, Kelly Clark, Norman E. Sharpless, Wolfgang Bergmeier, Weihe Zhang, Xiaodong Wang, Deborah DeRyckere, Stephen Frye, Douglas Graham. A small molecule Mer tyrosine kinase inhibitor (UNC MerTKi) effectively inhibits growth of murine melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 947. doi:10.1158/1538-7445.AM2014-947