Targeting GAS6 in cancer, fibrosis and viral infection
The growth-arrest specific 6 (GAS6) protein has emerged in recent years as an attractive target for drug development primarily because it is the sole ligand for the AXL receptor tyrosine kinase, which plays critical roles in cancer, fibrosis, and viral infection.
Furthermore, research has shown that elevated GAS6 levels and activation of AXL signalling both correlate with poor prognosis, more invasive disease, and resistance to chemotherapy, radiation, and targeted therapies.
Evidence that GAS6, via AXL activation, is a key driver of epithelial-mesenchymal transition (EMT) has heightened interest in efforts to inhibit this critical ligand-receptor interaction because research has found many cancers utilise EMT during invasion and metastasis, as well as chemoresistance. Additional research has revealed the relationship between GAS6-mediated AXL signalling and the DNA damage response. Modulation of this biological process is a compelling prospect for drug development because diminished signalling may boost the efficacy of chemotherapies in a variety of human cancers.
In addition to its role in regulating EMT, the GAS6/AXL pathway can also modulate tumour growth and progression via regulation of fibrosis. Recent studies have indicated that GAS6 concentration correlates directly to liver stiffness in patients with fibrosis and that the ligand may play a role in the pathogenesis and progression of steatohepatitis and fibrosis.
Adding to the appeal of GAS6 as a drug target is the relatively recent discovery that GAS6 inhibitors of TAM have antiviral properties that may help reduce transmission of some of the most troublesome emerging viruses. These include dengue, West Nile, Ebola, lentivirus, and most recently, Zika.
TAM and GAS6 background
The TAM family of receptor tyrosine kinases (RTKs) derives its name from the first letters of its constituents – TYRO3, AXL, and MERTK. Research has implicated all three receptors in tumour growth, but AXL has been shown to play the leading role in driving cancer metastasis and acquired drug resistance.