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The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer
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 b...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10287694/ https://www.ncbi.nlm.nih.gov/pubmed/37349576 http://dx.doi.org/10.1038/s42003-023-05045-0 |
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author | 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 |
author_facet | 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 |
author_sort | Yeo, Xun Hui |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10287694 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-102876942023-06-24 The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer 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 Commun Biol Article 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. Nature Publishing Group UK 2023-06-22 /pmc/articles/PMC10287694/ /pubmed/37349576 http://dx.doi.org/10.1038/s42003-023-05045-0 Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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 The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer |
title | The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer |
title_full | The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer |
title_fullStr | The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer |
title_full_unstemmed | The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer |
title_short | The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer |
title_sort | effect of inhibition of receptor tyrosine kinase axl on dna damage response in ovarian cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10287694/ https://www.ncbi.nlm.nih.gov/pubmed/37349576 http://dx.doi.org/10.1038/s42003-023-05045-0 |
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