The role of the AXL Receptor Tyrosine Kinase in the DNA damage response
Nominating Supervisor: Amato Giaccia
Second Supervisor: Ester Hammond
The Axl receptor tyrosine kinase is a critical driver of tumour progression and drug resistance, and has resulted in combining Axl inhibitors with both targeted and cytotoxic therapies. Previous data from the lab suggests that inhibiting Axl induces a DNA damage response, as evidenced by elevated gH2AX levels. To further understand this relationship, between Axl and DNA damage signalling, we performed a reverse phase protein array (RPPA) on wild-type cell lines with Axl either genetically or biologically inhibited. We found Akt, mTor, and P70SK6 to be differentially expressed as well as key components of the DNA damage response (XRCC1/Chk2) and some pro-apoptotic members of the Bcl-2 pathway (BAX/BID). This project will focus on identifying the molecular pathways involved in AXL regulation of DNA damage and pro-apoptotic genes. In addition, the role of Axl signalling in the induction of the cGas/Sting pathway by DNA damage will also be investigated.
We have developed soluble Axl receptors that act as a trap for the ligand Gas6 and have taken them from preclinical animal models into clinical trials in patients with metastatic ovarian cancer. This is an important pathway in metastatic cancer. Students will be trained in yeast surface display, mutagenesis, flow cytometry and tumor biology. Students will present their work at lab meetings, departmental seminars, and national and international conferences.
Direct Regulation of GAS6/AXL signalling by HIF promotes renal metastasis through SRC and MET. Rankin EB, Fuh KC, Castellini L, Viswanathan K, Finger EC, Diep AN, LaGory EL, Kariolis MS, Chan A, Lindgren D, Axelson H, Miao YR, Krieg AJ, Giaccia AJ. Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13373-8.
An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis. Kariolis MS, Miao YR, Jones DS 2nd, Kapur S, Mathews II, Giaccia AJ, Cochran JR. Nat Chem Biol. 2014 Nov;10(11):977-83.
Reprogramming the immunological microenvironment through radiation and targeting Axl. Aguilera TA, Rafat M, Castellini L, Shehade H, Kariolis MS, Hui AB, Stehr H, von Eyben R, Jiang D, Ellies LG, Koong AC, Diehn M, Rankin EB, Graves EE, Giaccia AJ. Nat Commun. 2016 Dec 23;7:13898.