Human Cutaneous Melanomas Lacking MITF and Melanocyte Differentiation Antigens Express a Functional Axl Receptor Kinase

Abstract

Axl, a member of the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases, displays an increasingly important role in carcinogenesis. Analysis of 58 cutaneous melanoma lines indicated that Axl was expressed in 38% of them, with significant overrepresentation in NRAS- compared with BRAF-mutated tumors. Axl activation could be induced by autocrine production of its ligand, Gas6, in a significant fraction of Axl-positive tumors. Pearson's correlation analysis on expression data from five data sets of melanoma lines identified several transcripts correlating positively or negatively with Axl. By functionally grouping genes, those inversely correlated were involved in melanocyte development and pigmentation, whereas those positively correlated were involved in motility, invasion, and microenvironment interactions. Accordingly, Axl-positive melanomas did not express microphthalmia transcription factor (MITF) and melanocyte differentiation antigens (MDAs) such as MART-1 and gp100 and possessed a greater in vitro invasive potential compared with Axl-negative ones. Motility, invasivity, and ability to heal a wound or to migrate across an endothelial barrier were inhibited in vitro by Axl knockdown. Pharmacological inhibition of Axl using the selective inhibitor R428 had comparable effects in reducing migration and invasion. These results suggest that targeted inhibition of Axl signaling in the subset of melanomas lacking MITF and MDAs may represent a novel therapeutic strategy.

Evaluating Melanoma Drug Response and Therapeutic Escape with Quantitative Proteomics

“…Although PDGFR-␤ was critical for therapeutic escape in this context, the expression of RTKs in melanoma is highly heterogeneous, and could be ultimately patient/tumor-specific. The multiplicity of RTK expression in melanoma cell lines and tumors is suggestive of many potential escape mechanisms and again underscores the need for multiplexed screening platforms such as the one described here (45,46). With regard to the future clinical application of LC-MRM, a situation can be envisaged where the interrogation of adaptive RTK signaling could be used to design personalized, patient-specific MEK/RTK inhibitor combinations that limit the onset of resistance.…”

MERTK receptor tyrosine kinase is a therapeutic target in melanoma

“…have previously described melanoma cell expression and secretion of GAS6, the common ligand for all members of the TAM family of proteins, suggesting a method of autocrine and/or paracrine activation of MERTK (18). Since expression of MERTK by melanoma cells increases during progression from primary to metastatic melanoma, it would be interesting to determine whether corresponding increases in GAS6 levels occur in serum from patients with metastatic melanoma, implicating serum GAS6 levels as a potential early marker of melanoma progression, as in other cancers (32).…”

“…TYRO3 was identified as an overexpressed receptor in melanoma, a regulator of MITF, and a contributor to the proliferative, antiapoptotic, chemoresistant, and tumorigenic phenotypes of melanoma cells (17). In another study, AXL was commonly expressed in NRAS-mutant melanomas lacking MITF expression and contributed to a migratory and invasive phenotype (18). In addition, Sensi et al found that melanoma cells often secrete GAS6, a ligand of TAM receptors, indicating a mechanism of TAM autocrine signaling in melanoma.…”

Beyond BRAF: Targeting Ras in Melanoma

“…A recent retrospective analysis of patients treated with high dose interleukin (IL)-2 demonstrated that the majority of the responders were NRAS mutant and that patients with either BRAF mutant or BRAF/NRAS wild-type melanoma were less likely to respond (21). Another class of drugs currently undergoing evaluation for multiple cancer types are receptor tyrosine kinase (RTK) inhibitors, and there is evidence that NRAS mutant melanomas may be enriched for expression of RTKs such as c-MET and Axl (22).…”