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Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer

BACKGROUND: Epithelial ovarian cancer (EOC) is a highly lethal malignancy. Improvement in genetic characterization of EOC patients is required to propose new potential targets, since surgical resection coupled to chemotherapy, presents several limits such as cancer recurrence and drug resistance. Ta...

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Autores principales: Guan, Luyao, Li, Zhang, Xie, Feifei, Pang, Yuzhi, Zhang, Chenyun, Tang, Haosha, Zhang, Hao, Chen, Chun, Zhan, Yaying, Zhao, Ting, Jiang, Hongyuan, Jia, Xiaona, Wang, Yuexiang, Lu, Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092606/
https://www.ncbi.nlm.nih.gov/pubmed/32293499
http://dx.doi.org/10.1186/s13046-020-01557-3
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author Guan, Luyao
Li, Zhang
Xie, Feifei
Pang, Yuzhi
Zhang, Chenyun
Tang, Haosha
Zhang, Hao
Chen, Chun
Zhan, Yaying
Zhao, Ting
Jiang, Hongyuan
Jia, Xiaona
Wang, Yuexiang
Lu, Yuan
author_facet Guan, Luyao
Li, Zhang
Xie, Feifei
Pang, Yuzhi
Zhang, Chenyun
Tang, Haosha
Zhang, Hao
Chen, Chun
Zhan, Yaying
Zhao, Ting
Jiang, Hongyuan
Jia, Xiaona
Wang, Yuexiang
Lu, Yuan
author_sort Guan, Luyao
collection PubMed
description BACKGROUND: Epithelial ovarian cancer (EOC) is a highly lethal malignancy. Improvement in genetic characterization of EOC patients is required to propose new potential targets, since surgical resection coupled to chemotherapy, presents several limits such as cancer recurrence and drug resistance. Targeted therapies have more efficacy and less toxicity than standard treatments. One of the most relevant cancer-specific actionable targets are protein tyrosine kinases (PTKs) whose role in EOC need to be better investigated. METHODS: EOC genomic datasets are retrieved and analyzed. The biological and clinical significance of RET genomic aberrations in ovarian cancer context are investigated by a series of in vitro and in vivo experiments. RESULTS: Epithelial ovarian cancer sequencing projects identify recurrent genomic RET missense mutations in 1.98% of patients, ranking as the top-five hit among the 100 receptor tyrosine kinases-encoding genes. RET mutants R693H and A750T show oncogenic transformation properties in NIH3T3 cells. Introduction of the RET mutants into human EOC cells increases RET signaling, cell viability, anchorage-independent cell growth and tumor xenograft growth in nude mice, demonstrating that they are activating mutations. RET mutants significantly enhance the activation of RET and its downstream MAPK and AKT signaling pathway in ovarian cancer cells. Vandetanib, a clinical approved RET inhibitor, inhibits the cell viability and decreases the activation of RET-MAPK signaling pathways in EOC cells expressing oncogenic RET mutants. CONCLUSIONS: The discovery of RET pathogenic variants in the EOC patients, suggests a previously underestimated role for RET in EOC tumorigenesis. The identification of the gain-of-function RET mutations in EOC highlights the potential use of RET in targeted therapy to treat ovarian cancer patients.
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spelling pubmed-70926062020-03-27 Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer Guan, Luyao Li, Zhang Xie, Feifei Pang, Yuzhi Zhang, Chenyun Tang, Haosha Zhang, Hao Chen, Chun Zhan, Yaying Zhao, Ting Jiang, Hongyuan Jia, Xiaona Wang, Yuexiang Lu, Yuan J Exp Clin Cancer Res Research BACKGROUND: Epithelial ovarian cancer (EOC) is a highly lethal malignancy. Improvement in genetic characterization of EOC patients is required to propose new potential targets, since surgical resection coupled to chemotherapy, presents several limits such as cancer recurrence and drug resistance. Targeted therapies have more efficacy and less toxicity than standard treatments. One of the most relevant cancer-specific actionable targets are protein tyrosine kinases (PTKs) whose role in EOC need to be better investigated. METHODS: EOC genomic datasets are retrieved and analyzed. The biological and clinical significance of RET genomic aberrations in ovarian cancer context are investigated by a series of in vitro and in vivo experiments. RESULTS: Epithelial ovarian cancer sequencing projects identify recurrent genomic RET missense mutations in 1.98% of patients, ranking as the top-five hit among the 100 receptor tyrosine kinases-encoding genes. RET mutants R693H and A750T show oncogenic transformation properties in NIH3T3 cells. Introduction of the RET mutants into human EOC cells increases RET signaling, cell viability, anchorage-independent cell growth and tumor xenograft growth in nude mice, demonstrating that they are activating mutations. RET mutants significantly enhance the activation of RET and its downstream MAPK and AKT signaling pathway in ovarian cancer cells. Vandetanib, a clinical approved RET inhibitor, inhibits the cell viability and decreases the activation of RET-MAPK signaling pathways in EOC cells expressing oncogenic RET mutants. CONCLUSIONS: The discovery of RET pathogenic variants in the EOC patients, suggests a previously underestimated role for RET in EOC tumorigenesis. The identification of the gain-of-function RET mutations in EOC highlights the potential use of RET in targeted therapy to treat ovarian cancer patients. BioMed Central 2020-03-23 /pmc/articles/PMC7092606/ /pubmed/32293499 http://dx.doi.org/10.1186/s13046-020-01557-3 Text en © The Author(s) 2020 Open AccessThis 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/. The Creative Commons Public Domain Dedication waiver (http://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
Guan, Luyao
Li, Zhang
Xie, Feifei
Pang, Yuzhi
Zhang, Chenyun
Tang, Haosha
Zhang, Hao
Chen, Chun
Zhan, Yaying
Zhao, Ting
Jiang, Hongyuan
Jia, Xiaona
Wang, Yuexiang
Lu, Yuan
Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer
title Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer
title_full Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer
title_fullStr Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer
title_full_unstemmed Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer
title_short Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer
title_sort oncogenic and drug-sensitive ret mutations in human epithelial ovarian cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092606/
https://www.ncbi.nlm.nih.gov/pubmed/32293499
http://dx.doi.org/10.1186/s13046-020-01557-3
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