Abstract
Expression of MERTK promotes melanoma cell survival and correlates with disease progression.
Major finding: Expression of MERTK promotes melanoma cell survival and correlates with disease progression.
Mechanism: GAS6-mediated MERTK activation stimulates oncogenic prosurvival and antiapoptotic pathways.
Impact: Inhibition of MERTK signaling induces apoptosis and reduces melanoma cell growth and invasion.
C-MER proto-oncogene tyrosine kinase (MERTK) is a member of the TAM (TYRO, AXL, MER) family of receptor tyrosine kinases and has been implicated in the growth and migration of several types of cancers, including leukemia and glioblastoma. Recent studies have shown that TAM receptors are also frequently activated in melanoma cell lines and that their ligand, growth arrest–specific 6 (GAS6), is secreted by melanoma cells, but the functional role of MERTK in melanoma progression remains unclear. Schlegel and colleagues found that MERTK expression in melanocytic lineage cells correlated with disease progression in melanoma tissue samples; MERTK levels were increased in primary tumors compared with benign nevi and were further elevated in metastatic melanoma tissues. In addition, MERTK was overexpressed in approximately 50% of melanoma cell lines independent of BRAF and RAS mutations. Stimulation of MERTK-expressing melanoma cell lines with GAS6 induced activation of multiple prosurvival and antiapoptotic pathways, including MAPK/ERK, phosphoinositide 3-kinase (PI3K)/AKT, and Janus–activated kinase (JAK)/STAT. Consistent with an oncogenic function for this kinase, knockdown of MERTK in melanoma cell lines impaired downstream signaling through STAT6, AKT, and ERK1/2, reduced colony formation, and suppressed melanoma xenograft growth. Targeted inhibition of MERTK using a selective, small-molecule tyrosine kinase inhibitor, UNC1062, similarly blocked MERTK-mediated prosurvival signaling and decreased anchorage-independent growth. Moreover, treatment with UNC1062 induced apoptosis and inhibited melanoma cell invasion, further supporting MERTK as a potential therapeutic target in melanoma. These results identify MERTK as an important regulator of melanoma cell growth and survival and support additional development of MERTK-targeted inhibitors for the treatment of this disease.
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