UNCOVERING THE NOVEL ROLES OF AXL AND THE ASSOCIATED THERAPEUTIC VULNERABILITIES

Abstract

AXL is a receptor tyrosine kinase that is often overexpressed in many cancers. It contributes to multiple tumour pathophysiology and drug resistance, making it an emerging therapeutic target. The first-in-class AXL inhibitor R428 (BGB321) was approved by the FDA for treatment of acute myeloid leukemia, and was also reported to show selective sensitivity towards ovarian cancers (OC) with a Mesenchymal molecular subtype. In this study, we further explored AXL’s role in mediating DNA damage responses by using OC as a disease model. AXL inhibition using R428 resulted in the increase DNA damage and this occurred concurrently with the upregulation of DNA damage response signaling molecules. Furthermore, our results showed that AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress, paving ways to the rationale for potential combinatory use of AXL and DNA damage repair inhibitors. Through SILAC Co-IP mass spectrometry, we uncovered a novel binding partner of AXL and lastly, proposed a protective role of cholesterol in shielding cancer cells against AXL inhibition-induced DNA damage.