DNA repair and cholesterol-mediated drug efflux induce dose-dependent chemoresistance in nutrient-deprived neuroblastoma cells

Chae, Soo Yeon; Nam, Dowoon; Hyeon, Do Young; Hong, Areum; Lee, Timothy Dain; Kim, Sujin; Im, Dongjoon; Hong, Jiwon; Kang, Chaewon; Lee, Ji Won; Hwang, Daehee; Lee, Sang Won; Kim, Hugh I.

doi:10.1016/j.isci.2021.102325

Cited by 3 publications

(1 citation statement)

References 61 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although these studies are beyond the context of cancer, they nonetheless support the proposed protective role of cholesterol against DNA damage. Increased cholesterol could also protect cells against DNA damage through cholesterol-mediated drug efflux 61 or through modulating signalling pathways 62 . As the protective role of cholesterol against DNA damage is not widely investigated, elucidating the mechanism of how cholesterol may limit DNA damage is essential.…”

Section: Discussionmentioning

confidence: 99%

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

Yeo,

Sundararajan,

et al. 2023

Commun Biol

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%