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MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC

BACKGROUND: Although the clinical application of PARP inhibitors has brought hope to ovarian cancer, the problem of its resistance has become increasingly prominent. Therefore, clinical experts have been focused on finding specific indicators and therapeutic targets that can be used for resistance m...

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Autores principales: Zhuang, Xucui, Xiao, Rourou, Fu, Yu, Yang, Bin, Fan, Junpeng, Lu, Funian, Qin, Tianyu, Yang, Xiaohang, Hu, Xingyuan, Yin, Jingjing, Li, Wenting, Kang, Xiaoyan, Chen, Gang, Hu, Dianxing, Sun, Chaoyang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10537967/
https://www.ncbi.nlm.nih.gov/pubmed/37759323
http://dx.doi.org/10.1186/s13578-023-01117-0
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author Zhuang, Xucui
Xiao, Rourou
Fu, Yu
Yang, Bin
Fan, Junpeng
Lu, Funian
Qin, Tianyu
Yang, Xiaohang
Hu, Xingyuan
Yin, Jingjing
Li, Wenting
Kang, Xiaoyan
Chen, Gang
Hu, Dianxing
Sun, Chaoyang
author_facet Zhuang, Xucui
Xiao, Rourou
Fu, Yu
Yang, Bin
Fan, Junpeng
Lu, Funian
Qin, Tianyu
Yang, Xiaohang
Hu, Xingyuan
Yin, Jingjing
Li, Wenting
Kang, Xiaoyan
Chen, Gang
Hu, Dianxing
Sun, Chaoyang
author_sort Zhuang, Xucui
collection PubMed
description BACKGROUND: Although the clinical application of PARP inhibitors has brought hope to ovarian cancer, the problem of its resistance has become increasingly prominent. Therefore, clinical experts have been focused on finding specific indicators and therapeutic targets that can be used for resistance monitoring of PARP inhibitors. RESULTS: By cfDNA detecting during Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer, we found the presence of MRE11:p.K464R mutation was strongly associated with acquired Olaparib resistance. Structural analysis revealed that the MRE11:p.K464R mutation is situated at a critical site where the MRE11 protein interacts with other biomolecules, leading to potential structural and functional abnormalities of MRE11 protein. Functionally, MRE11:p.K464R mutation enhanced the tolerance of Olaparib by reducing the DNA damage. Mechanistically, MRE11:p.K464R mutation improved the efficiency of DNA damage repair and induce Olaparib resistance by enhancing its binding activity with the interacting proteins (including RAD50 and RPS3). Among them, the enhanced binding of MRE11:p.K464R mutation to RAD50/RPS3 facilitated non-homologous end joining (NHEJ) repair in tumor cells, thereby expanding the scope of research into acquired resistance to PARP inhibitors. CONCLUSIONS: Our findings provide a theoretical basis for MRE11:p.K464R mutation as a specific indicator of resistance monitoring in Olaparib treatment, and the exploration of its resistance mechanism provides a novel insights for the formulation of combination ther therapies after Olaparib resistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01117-0.
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spelling pubmed-105379672023-09-29 MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC Zhuang, Xucui Xiao, Rourou Fu, Yu Yang, Bin Fan, Junpeng Lu, Funian Qin, Tianyu Yang, Xiaohang Hu, Xingyuan Yin, Jingjing Li, Wenting Kang, Xiaoyan Chen, Gang Hu, Dianxing Sun, Chaoyang Cell Biosci Research BACKGROUND: Although the clinical application of PARP inhibitors has brought hope to ovarian cancer, the problem of its resistance has become increasingly prominent. Therefore, clinical experts have been focused on finding specific indicators and therapeutic targets that can be used for resistance monitoring of PARP inhibitors. RESULTS: By cfDNA detecting during Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer, we found the presence of MRE11:p.K464R mutation was strongly associated with acquired Olaparib resistance. Structural analysis revealed that the MRE11:p.K464R mutation is situated at a critical site where the MRE11 protein interacts with other biomolecules, leading to potential structural and functional abnormalities of MRE11 protein. Functionally, MRE11:p.K464R mutation enhanced the tolerance of Olaparib by reducing the DNA damage. Mechanistically, MRE11:p.K464R mutation improved the efficiency of DNA damage repair and induce Olaparib resistance by enhancing its binding activity with the interacting proteins (including RAD50 and RPS3). Among them, the enhanced binding of MRE11:p.K464R mutation to RAD50/RPS3 facilitated non-homologous end joining (NHEJ) repair in tumor cells, thereby expanding the scope of research into acquired resistance to PARP inhibitors. CONCLUSIONS: Our findings provide a theoretical basis for MRE11:p.K464R mutation as a specific indicator of resistance monitoring in Olaparib treatment, and the exploration of its resistance mechanism provides a novel insights for the formulation of combination ther therapies after Olaparib resistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01117-0. BioMed Central 2023-09-27 /pmc/articles/PMC10537967/ /pubmed/37759323 http://dx.doi.org/10.1186/s13578-023-01117-0 Text en © The Author(s) 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Zhuang, Xucui
Xiao, Rourou
Fu, Yu
Yang, Bin
Fan, Junpeng
Lu, Funian
Qin, Tianyu
Yang, Xiaohang
Hu, Xingyuan
Yin, Jingjing
Li, Wenting
Kang, Xiaoyan
Chen, Gang
Hu, Dianxing
Sun, Chaoyang
MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC
title MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC
title_full MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC
title_fullStr MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC
title_full_unstemmed MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC
title_short MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC
title_sort mre11:p.k464r mutation mediates olaparib resistance by enhancing dna damage repair in hgsoc
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10537967/
https://www.ncbi.nlm.nih.gov/pubmed/37759323
http://dx.doi.org/10.1186/s13578-023-01117-0
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