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

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 BRAFmutated and BRAF wild-type models and irrespective of NRAS mutational status, implicating MERTK inhibition as a poten-tial 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 BRAFmutated 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.

MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

“…TAM receptor family member mediated regulation of the T cell response within the tumor is an active area of clinical and pre-clinical research (Myers et al, 2019;Wu et al, 2018a). Mertk specific inhibition has been shown to suppress tumor growth in murine solid tumor models (Cook et al, 2013;Sinik et al, 2018;Wu et al, 2018b). Additionally, suppression of TAM receptor signaling has been shown to increase the response to anti-PD-1 therapy in a murine tumor model, suggesting that it is mediated by a mechanism other than PD-1 signaling (Kasikara et al, 2019), as we have observed in our autoimmune models.…”

Blood retinal barrier and ocular pharmacokinetics: Considerations for the development of oncology drugs

“…Inhibition of MERTK has been found to promote innate tumor immunity by decreasing M2‐macrophage polarization and efferocytosis (removal of dead cells by phagocytes) (Boada‐Romero et al., 2020; Sinik et al., 2019). This mechanism offers the opportunity for targeted immunotherapy to treat cancer; however, the ocular expression of MERTK increases the difficulty for developing a targeted drug due to toxicity concerns.…”

Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

“…Only a subset of patients benefits from MEK inhibitors used as single agents, because they only produce cytostatic effects rather than cytotoxic effects, in NRAS mutant melanoma cells (13). MEK inhibitors are also associated with primary and acquired resistance as well as frequent toxicity-related adverse events (14,15). However, MEK inhibitors could deliver promising therapies when combined with inhibitors of other signaling mechanisms (12,(15)(16)(17).…”

“…MEK inhibitors are also associated with primary and acquired resistance as well as frequent toxicity-related adverse events (14,15). However, MEK inhibitors could deliver promising therapies when combined with inhibitors of other signaling mechanisms (12,(15)(16)(17). Currently, the MEK inhibitor FCN-159, which has 10-fold higher selectivity against activated MEK1/2 compared to trametinib, is being investigated as a single agent in a phase I clinical trial (NCT03932253).…”

“…Considering the lack of success of therapies targeting BRAF and MEK in NRAS mutant melanoma patients (42), recent efforts have been focused on finding other therapeutic targets and development of combination therapies. For example, inhibiting a novel NRAS-activating kinase (STK19) and combining MEK inhibitors with inhibitors of the MER receptor tyrosine kinase (MERTK), BET, and HDAC have been reported to block NRAS mutant melanoma growth in vitro and in vivo(15)(16)(17)43). In this study, we demonstrate that the combination of aRho/MRTF pathway inhibitor, CCG-222740 and the MEK inhibitor trametinib synergistically inhibited viability of a subset of NRAS mutant melanoma cells and also induced apoptosis in cell with highly activated Rho/MRTF pathway.…”