- AXL is a tyrosine kinase membrane receptor that signals via the phosphatidylinositol-3-kinases (PI3K), mitogen-activated protein kinases (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. Increased expression of AXL in cancer is often the result of pharmacological selective pressure to a number of chemo- 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 epidermal growth factor receptor (EGFR), including lung, head and neck and triple negative breast cancer, AXL dimerizes with this receptor and initiates signaling that circumvent the antitumor effects of anti-EGFR therapies. Likewise AXL overexpression and dimerization with EGFR can overcome PI3K inhibition by activating the phospholipase C-gamma (PLCγ)-PKC cascade that in turn sustains mammalian target of rapamycin complex 1 (mTORC1) activity. The causative role of AXL in inducing resistance drug resistance is underscored by the fact that 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 co-targeting AXL in this setting would potentially overcome drug resistance. The use of AXL inhibitors should be considered in the clinic.