AXL Receptor in Cancer Metastasis and Drug Resistance: When Normal Functions Go Askew

Simple Summary AXL is a member of the TAM (TYRO3, AXL, MER) family of receptor tyrosine kinases. In normal physiological conditions, AXL is involved in removing dead cells and their remains, and limiting the duration of immune responses. Both functions are utilized by cancers in the course of tumour progression. Cancer cells use the AXL pathway to detect toxic environments and to activate molecular mechanisms, thereby ensuring their survival or escape from the toxic zone. AXL is instrumental in controlling genetic programs of epithelial-mesenchymal and mesenchymal-epithelial transitions, enabling cancer cells to metastasize. Additionally, AXL signaling suppresses immune responses in tumour microenvironment and thereby helps cancer cells to evade immune surveillance. The broad role of AXL in tumour biology is the reason why its inhibition sensitizes tumours to a broad spectrum of anti-cancer drugs. In this review, we outline molecular mechanisms underlying AXL function in normal tissues, and discuss how these mechanisms are adopted by cancers to become metastatic and drug-resistant. The TAM proteins TYRO3, AXL, and MER are receptor tyrosine kinases implicated in the clearance of apoptotic debris and negative regulation of innate immune responses. AXL contributes to immunosuppression by terminating the Toll-like receptor signaling in dendritic cells, and suppressing natural killer cell activity. In recent years, AXL has been intensively studied in the context of cancer. Both molecules, the receptor, and its ligand GAS6, are commonly expressed in cancer cells, as well as stromal and infiltrating immune cells. In cancer cells, the activation of AXL signaling stimulates cell survival and increases migratory and invasive potential. In cells of the tumour microenvironment, AXL pathway potentiates immune evasion. AXL has been broadly implicated in the epithelial-mesenchymal plasticity of cancer cells, a key factor in drug resistance and metastasis. Several antibody-based and small molecule AXL inhibitors have been developed and used in preclinical studies. AXL inhibition in various mouse cancer models reduced metastatic spread and improved the survival of the animals. AXL inhibitors are currently being tested in several clinical trials as monotherapy or in combination with other drugs. Here, we give a brief overview of AXL structure and regulation and discuss the normal physiological functions of TAM receptors, focusing on AXL. We present a theory of how epithelial cancers exploit AXL signaling to resist cytotoxic insults, in order to disseminate and relapse.