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Title: The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer
Authors: Yeo, Xun Hui
Sundararajan, Vignesh 
Wu, Zhengwei 
Phua, Zi Jin Cheryl
Ho, Yin Ying
Peh, Kai Lay Esther
Chiu, Yi-Chia
Tan, Tuan Zea 
Kappei, Dennis 
Ho, Ying Swan
Tan, David Shao Peng 
Tam, Wai Leong 
Huang, Ruby Yun-Ju 
Issue Date: 2023
Publisher: Springer Science and Business Media LLC
Citation: Yeo, Xun Hui, Sundararajan, Vignesh, Wu, Zhengwei, Phua, Zi Jin Cheryl, Ho, Yin Ying, Peh, Kai Lay Esther, Chiu, Yi-Chia, Tan, Tuan Zea, Kappei, Dennis, Ho, Ying Swan, Tan, David Shao Peng, Tam, Wai Leong, Huang, Ruby Yun-Ju (2023). The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer. Communications Biology 6 (1). ScholarBank@NUS Repository.
Abstract: AbstractAXL 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.
Source Title: Communications Biology
ISSN: 2399-3642
DOI: 10.1038/s42003-023-05045-0
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