title: Key Roles of AXL and MER Receptor Tyrosine Kinases in Resistance to Multiple Anticancer Therapies.
abstract: A major challenge in anticancer treatment is the pre-existence or emergence of resistance to therapy. AXL and MER are two members of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which, when activated, can regulate tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interactions. An increasing body of evidence strongly suggests that these receptors play major roles in resistance to targeted therapies and conventional cytotoxic agents. Multiple resistance mechanisms exist, including the direct and indirect crosstalk of AXL and MER with other receptors and the activation of feedback loops regulating AXL and MER expression and activity. These mechanisms may be innate, adaptive, or acquired. A principal role of AXL appears to be in sustaining a mesenchymal phenotype, itself a major mechanism of resistance to diverse anticancer therapies. Both AXL and MER play a role in the repression of the innate immune response which may also limit response to treatment. Small molecule and antibody inhibitors of AXL and MER have recently been described, and some of these have already entered clinical trials. The optimal design of treatment strategies to maximize the clinical benefit of these AXL and MER targeting agents are discussed in relation to the different cancer types and the types of resistance encountered. One of the major challenges to successful development of these therapies will be the application of robust predictive biomarkers for clear-cut patient stratification.
authors.affiliation: Oncology Translational and Clinical Research, Institut de Recherches Servier (IdRS), 125 Chemin de Ronde, 78290, Croissy, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Schoumacher
authors.affiliation: Oncology Translational and Clinical Research, Institut de Recherches Internationales Servier (IRIS), 50 rue Carnot, 92284, Suresnes cedex, France. mike.burbridge@servier.com.
authors.forename: Mike
authors.initials: M
authors.lastname: Burbridge
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000627:therapeutic use; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: AXL; Cancer; Drug resistance; Epithelial-to-mesenchymal transition; Immunomodulation; MER