MERTK receptor tyrosine kinase is a therapeutic target in melanoma

Abstract

Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. Although recent therapeutic advances have prolonged patient survival, the prognosis remains dismal. C-MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that MERTK expression correlates with disease progression. MERTK expression was highest in metastatic melanomas, followed by primary melanomas, while the lowest expression was observed in nevi. IntroductionAlthough early cutaneous melanoma is usually curable with surgery, distant metastatic melanoma is an aggressive cancer with a median overall survival time of less than 1 year. In 2012, over 75,000 new melanoma diagnoses were expected and over 9,000 deaths were projected (1). Advances in the understanding of distinct melanoma subtypes as well as melanoma immunobiology have resulted in 2 FDA-approved therapies for metastatic melanoma in 2011: vemurafenib, an inhibitor of mutant BRAF -an oncogene present in approximately 50% of melanomas -and ipilimumab, a monoclonal antibody that targets CTLA-4 (2-4). Despite these rather impressive developments, the overall clinical benefit is limited to either small subgroups of patients who

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

“…68 Furthermore, aberrant Mer expression at low levels may be important, for example, for invasive properties of tumor cells. 69,70 However, Mer and CNS positivity correlated only in t(1;19) patients.…”

Mer receptor tyrosine kinase is a therapeutic target in pre–B-cell acute lymphoblastic leukemia

“…13 Transgenic Mer expression in mice results in the development of Tcell and biphenotypic lymphoblastic leukemia and lymphoma. 14 Mer activates antiapoptotic signaling proteins, including AKT and ERK1/2, [15][16][17] and promotes tumorigenic phenotypes in several other tumor types, including non-small-cell lung cancer, 18 melanoma, 19 and acute myeloid leukemia. 20 Here, we present data demonstrating increased Mer protein in E2A-PBX1…”

Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer

“…Increased expression of AXL has been reported in lung, breast, ovarian, gastric, pancreatic, and prostate cancers; leukemias and lymphomas; melanoma; and glioblastoma multiforme (4,5). Increased MER expression is associated with leukemias, lymphomas, melanoma, rhabdomyosarcomas, and gastric and prostate cancers (4)(5)(6). AXL and MER expression also has been directly correlated with poor prognosis in cancer (6)(7)(8)(9).…”

“…Multiple studies have demonstrated AXL and MER function in survival, invasion, and metastasis in a variety of tumors (12-15); thus, attention has focused on the pharmacologic targeting of AXL and MER in cancer. Axl and Mer share structural homology in the kinase domain with other tyrosine kinases, including conserved molecular interactions with ATP; however, several unique features of the active site allow for selective inhibition (16), and small-molecule inhibitors as well as biologics are in preclinical development (6,(16)(17)(18)(19).Axl and Mer are associated with another distinct feature of cancer-inflammation. Tumor-promoting inflammation has been described as an enabling characteristic that promotes the acquisition of cancer hallmarks and orchestrates tumor progression (20).…”

“…Increased MER expression is associated with leukemias, lymphomas, melanoma, rhabdomyosarcomas, and gastric and prostate cancers (4)(5)(6). AXL and MER expression also has been directly correlated with poor prognosis in cancer (6)(7)(8)(9). Moreover, ectopic expression of AXL has been shown to confer resistance to EGF receptor therapy in lung cancer (10,11).…”