IntroductionThe Mer (Mertk, Nyk, c-Eyk) receptor tyrosine kinase is a transmembrane receptor consisting of an extracellular domain with 2 immunoglobulin-like and 2 membrane proximal fibronectin III motifs, a transmembrane region, and an intracellular tyrosine kinase domain. 1,2 These motifs place Mer in the same tyrosine kinase subfamily as Axl 3 and Tyro-3/Sky. 4,5 Mer, Axl, and Tyro-3 share the same ligand, 6,7 Gas6, which has significant homology to the negative coregulator of the blood coagulation pathway protein S. 8 Abnormal expression or activity of the Mer tyrosine kinase may play a role in tumorigenesis. The avian Mer ortholog, eyk, was discovered first as the oncogene in acute avian retrovirus RPL30. The constitutively active tyrosine kinase domain of v-eyk causes fibrosarcomas, endotheliomas, and visceral lymphomatosis in chickens. 9,10 Overexpression of murine Mer tyrosine kinase transforms BaF3 lymphocytes 11 and overexpression of human Mer transforms NIH3T3 cells. 12 Several human cancers overexpress Mer, including mantle cell lymphomas, 13 alveolar rhabdomyosarcomas, 14 gastric cancer, 15 and pituitary adenomas. 16 Mer is also ectopically expressed in pediatric T-cell acute lymphoblastic leukemia, 17 and a Mer transgenic mouse model with ectopic expression of Mer in thymocytes and lymphocytes develops T-cell lymphoblastic leukemia/lymphoma. 18 Axl and Tyro-3 also transform cells in vitro 3,4 and are overexpressed in a spectrum of human cancers.In addition to abnormal function of Mer in cancer, a physiologic role for Mer has recently been described in macrophages. Mer, Axl, and Tyro-3 have been shown to limit the extent of macrophage activation in response to an immune stimulus. 19,20 Mer also plays a significant role in the ability of macrophages to clear apoptotic cells, 21 and Mer deficiency has been linked to the development of autoimmune disorders in mice. Lack of Mer receptor causing defective macrophage apoptotic cell clearance in the Royal College of Surgeons (RCS) rat has also been implicated in the development of retinitis pigmentosa. 22 Interestingly, Mer gene mutations have been defined in a subset of humans with retinitis pigmentosa. 23 Furthermore, a physiologic role for the Mer tyrosine kinase has been described for the normal function of platelets. The interaction of Gas6 with Mer, Axl, and Tyro-3 is important in platelet degranulation and aggregation in response to known agonists. Mice lacking either Gas6 or Mer protein have impaired platelet aggregation in vitro and diminished clot stability in vivo. [24][25][26] A delicate balance of ligand interaction with a tyrosine kinase receptor is necessary to maintain normal tyrosine kinase function without causing overactivation, which could result in human disease. One means of regulating tyrosine kinase activation is through proteolytic cleavage of the membrane-bound protein.Through this process, the total number of membrane-bound receptors is reduced. In addition, the soluble cleavage product may function as a decoy receptor and seques...
Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon, and pancreatic cancers combined. Current research suggests that standard chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT, and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway—involving AKT, CREB, Bcl-xL, survivin, and Bcl-2—downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that shRNA knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl play complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.
We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.
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
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