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|Ref Type||Journal Article|
|Authors||Sinik L, Minson KA, Tentler JJ, Carrico J, Bagby SM, Robinson WA, Kami R, Burstyn-Cohen T, Eckhardt SG, Wang X, Frye SV, Earp HS, DeRyckere D, Graham DK|
|Title||Inhibition of MERTK Promotes Suppression of Tumor Growth in BRAF Mutant and BRAF Wild-Type Melanoma.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|UNC2025||UNC-2025|UNC 2025||FLT3 Inhibitor 62 MERTK Inhibitor 13||UNC2025 inhibits FLT3 and MERTK, which may result in decreased growth of MER-dependent and FLT3-dependent tumor cells (PMID: 25068800, PMID: 30482852).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|BRAF mutant||melanoma||predicted - sensitive||UNC2025 + Vemurafenib||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, the combination therapy of UNC2025 and Zelboraf (vemurafenib) resulted in greater inhibition of colony formation and apoptotic induction in melanoma cells harboring a BRAF mutation in culture and led to a higher degree of tumor growth inhibition in a patient derived xenograft (PDX) model of melanoma with a BRAF mutation when compared to either therapy alone (PMID: 30482852).||30482852|
|NRAS mutant||melanoma||predicted - sensitive||Cobimetinib + UNC2025||Preclinical - Cell culture||Actionable||In a preclinical study, the combination therapy of UNC2025 and Cotellic (cobimetinib) resulted in greater inhibition of colony formation and apoptotic induction in melanoma cells harboring an NRAS mutation in culture when compared to either therapy alone (PMID: 30482852).||30482852|