The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer

Abstract

AXL is a receptor tyrosine kinase that is often overexpressed in cancers. It contributes to pathophysiology in cancer progression and therapeutic resistance, making it an emerging therapeutic target. The first-in-class AXL inhibitor bemcentinib (R428/BGB324) has been granted fast track designation by the U.S. Food and Drug Administration (FDA) in STK11-mutated advanced metastatic non-small cell lung cancer 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 of DNA damage with the concurrent upregulation of DNA damage response signalling molecules. Furthermore, AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress. Combinatory use of AXL and ATR inhibitors showed additive effects in OC. Through SILAC co-immunoprecipitation mass spectrometry, we identified a novel binding partner of AXL, SAM68, whose loss in OC cells harboured phenotypes in DNA damage responses similar to AXL inhibition. In addition, AXL- and SAM68-deficiency or R428 treatment induced elevated levels of cholesterol and upregulated genes in the cholesterol biosynthesis pathway. There might be a protective role of cholesterol in shielding cancer cells against DNA damage induced by AXL inhibition or SMA68 deficiency.

Drug resistance in ovarian cancer: from mechanism to clinical trial

“…Moreover, the role of the GAS/AXL pathway in DDR has gradually been revealed in ovarian cancer. Inhibition of AXL (via bemcentinib or MYD1-72) resensitizes ovarian cancer cells to platinum, ATR inhibitors (ATRis) and PARPis by increasing DNA damage and inducing RS [130][131][132]. Furthermore, GAS6/AXL signaling promotes the generation of an immunosuppressive TME by modulating the expression of MHC and PD-L1 in neoplastic cells, increasing the secretion of immunosuppressive chemokines, and interfering with the infiltration of immune cells [133].…”

Biomarkers in Ovarian Cancer: Towards Personalized Medicine

“…This receptor’s role in promoting cell survival and inhibiting apoptosis further underscores its significance in OC progression. Thus, the AXL receptor can be employed dually: (i) exploring AXL inhibitors as potential therapeutic agents to counteract the aggressive features of OC [ 151 , 152 ], and (ii) targeting AXL receptor within nanodelivery systems to improve drug incorporation and release efficacies.…”

The golden key to open mystery boxes of SMARCA4-deficient undifferentiated thoracic tumor: focusing immunotherapy, tumor microenvironment and epigenetic regulation

“…AXL is a receptor tyrosine kinase that is often overexpressed in cancers [ 43 ]. Bemcentinib restored pembrolizumab sensitivity of STK11/LKB1 mutant NSCLC through expansion of PD-1 + CD8 + T cells [ 44 ], and it has been granted fast track designation by the U.S. Food and Drug Administration (FDA) in STK11 mutated advanced metastatic NSCLC [ 43 ].…”