title: Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy.
abstract: AXL is a tyrosine kinase membrane receptor that signals via PI3K, MAPK, and protein kinase C (PKC), among other pathways. AXL has oncogenic potential and interacts with other membrane receptors, depending on their relative abundance and availability. The increased expression of AXL in cancer is often the result of pharmacologic selective pressure to a number of chemotherapies and targeted therapies and acts as a mechanism of acquired drug resistance. This resistance phenotype, frequently accompanied by epithelial-to-mesenchymal transition, can be reversed by AXL inhibition. In tumors with high levels of EGFR, including lung, head and neck, and triple-negative breast cancer, AXL dimerizes with this receptor and initiates signaling that circumvents the antitumor effects of anti-EGFR therapies. Likewise, AXL overexpression and dimerization with EGFR can overcome PI3K inhibition by activating the phospholipase C-γ-PKC cascade that, in turn, sustains mTORC1 activity. The causative role of AXL in inducing drug resistance is underscored by the fact that the suppression of AXL restores sensitivity to these agents. Hence, these observations indicate that AXL is selectively expressed in tumor cells refractory to therapy and that cotargeting AXL in this setting would potentially overcome drug resistance. The use of AXL inhibitors should be considered in the clinic.
authors.affiliation: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. scaltrim@mskcc.org baselgaj@mskcc.org.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Elkabets
authors.affiliation: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. scaltrim@mskcc.org baselgaj@mskcc.org.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D057170:Translational Research, Biomedical; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human