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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/171552 |
| _version_ | 1826111150292467712 |
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| author | Yeo, Xun Hui Sundararajan, Vignesh Wu, Zhengwei Phua, Cheryl Zi Jin Ho, Yin Ying Peh, Esther Kai Lay Chiu, Yi-Chia Tan, Tuan Zea Kappei, Dennis Ho, Ying Swan Tan, David Shao Peng Tam, Wai Leong Huang, Ruby Yun-Ju |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Yeo, Xun Hui Sundararajan, Vignesh Wu, Zhengwei Phua, Cheryl Zi Jin Ho, Yin Ying Peh, Esther Kai Lay 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 | NTU |
| 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. |
| first_indexed | 2024-10-01T02:45:56Z |
| format | Journal Article |
| id | ntu-10356/171552 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:45:56Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1715522023-10-30T15:31:50Z The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer Yeo, Xun Hui Sundararajan, Vignesh Wu, Zhengwei Phua, Cheryl Zi Jin Ho, Yin Ying Peh, Esther Kai Lay Chiu, Yi-Chia Tan, Tuan Zea Kappei, Dennis Ho, Ying Swan Tan, David Shao Peng Tam, Wai Leong Huang, Ruby Yun-Ju School of Biological Sciences Genome Institute of Singapore, A*STAR Cancer Science Institute of Singapore, NUS Yong Loo Lin School of Medicine, NUS Science::Biological sciences Ovary Tumor AXL Receptor Tyrosine Kinase 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. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work was supported by the Ministry of Science and Technology Taiwan (108-2320-B-002 -013 -MY3) to R.Y.-J.H. R.Y.-J.H is currently supported by the Yushan Scholar Programme by the Ministry of Education, Taiwan (NTU-110V0402). This research is further supported by the National Medical Research Council, Singapore (OFIRG17may061, OFIRG19nov-0106), National Research Foundation, Singapore (NRF-NRFF2015-04, NRF-CRP22-2019-0003, NRF-CRP23-2019-0004), Agency for Science, Technology and Research, Singapore, and the Singapore Ministry of Education under its Research Centres of Excellence initiative. This work was supported by funding from the Singapore Ministry of Health’s National Medical Research Council under its Centre Grant scheme to the National University Cancer Institute and Clinician Scientist Award (NMRC/CSA-INV/0016/2017, to D.S.P.T.) and by funding from the Pangestu Family Foundation Gynaecological Cancer Research Fund. 2023-10-30T07:40:29Z 2023-10-30T07:40:29Z 2023 Journal Article Yeo, X. H., Sundararajan, V., Wu, Z., Phua, C. Z. J., Ho, Y. Y., Peh, E. K. L., Chiu, Y., Tan, T. Z., Kappei, D., Ho, Y. S., Tan, D. S. P., Tam, W. L. & Huang, R. Y. (2023). The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer. Communications Biology, 6(1), 660-. https://dx.doi.org/10.1038/s42003-023-05045-0 2399-3642 https://hdl.handle.net/10356/171552 10.1038/s42003-023-05045-0 37349576 2-s2.0-85162785169 1 6 660 en OFIRG17may-061 OFIRG19nov-0106 NRF-NRFF2015-04 NRF-CRP22-2019-0003 NRF-CRP23-2019-0004 Communications Biology © The Author(s) 2023, corrected publication 2023. 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/. application/pdf |
| spellingShingle | Science::Biological sciences Ovary Tumor AXL Receptor Tyrosine Kinase Yeo, Xun Hui Sundararajan, Vignesh Wu, Zhengwei Phua, Cheryl Zi Jin Ho, Yin Ying Peh, Esther Kai Lay 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 | Science::Biological sciences Ovary Tumor AXL Receptor Tyrosine Kinase |
| url | https://hdl.handle.net/10356/171552 |
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