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Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance
Resistance to platinum-based chemotherapy is the major barrier to treating epithelial ovarian cancer. To improve patient outcomes, it is critical to identify the underlying mechanisms that promote platinum resistance. Emerging evidence supports the concept that platinum-based therapies are able to e...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695147/ https://www.ncbi.nlm.nih.gov/pubmed/26125441 |
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author | Nagaraj, Anil Belur Joseph, Peronne Kovalenko, Olga Singh, Sareena Armstrong, Amy Redline, Raymond Resnick, Kimberly Zanotti, Kristine Waggoner, Steven DiFeo, Analisa |
author_facet | Nagaraj, Anil Belur Joseph, Peronne Kovalenko, Olga Singh, Sareena Armstrong, Amy Redline, Raymond Resnick, Kimberly Zanotti, Kristine Waggoner, Steven DiFeo, Analisa |
author_sort | Nagaraj, Anil Belur |
collection | PubMed |
description | Resistance to platinum-based chemotherapy is the major barrier to treating epithelial ovarian cancer. To improve patient outcomes, it is critical to identify the underlying mechanisms that promote platinum resistance. Emerging evidence supports the concept that platinum-based therapies are able to eliminate the bulk of differentiated cancer cells, but are unable to eliminate cancer initiating cells (CIC). To date, the relevant pathways that regulate ovarian CICs remain elusive. Several correlative studies have shown that Wnt/β-catenin pathway activation is associated with poor outcomes in patients with high-grade serous ovarian cancer (HGSOC). However, the functional relevance of these findings remain to be delineated. We have uncovered that Wnt/β-catenin pathway activation is a critical driver of HGSOC chemotherapy resistance, and targeted inhibition of this pathway, which eliminates CICs, represents a novel and effective treatment for chemoresistant HGSOC. Here we show that Wnt/β-catenin signaling is activated in ovarian CICs, and targeted inhibition of β-catenin potently sensitized cells to cisplatin and decreased CIC tumor sphere formation. Furthermore, the Wnt/β-catenin specific inhibitor iCG-001 potently sensitized cells to cisplatin and decreased stem-cell frequency in platinum resistant cells. Taken together, our data is the first report providing evidence that the Wnt/β-catenin signaling pathway maintains stem-like properties and drug resistance of primary HGSOC PDX derived platinum resistant models, and therapeutic targeting of this pathway with iCG-001/PRI-724, which has been shown to be well tolerated in Phase I trials, may be an effective treatment option. |
format | Online Article Text |
id | pubmed-4695147 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-46951472016-01-26 Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance Nagaraj, Anil Belur Joseph, Peronne Kovalenko, Olga Singh, Sareena Armstrong, Amy Redline, Raymond Resnick, Kimberly Zanotti, Kristine Waggoner, Steven DiFeo, Analisa Oncotarget Research Paper Resistance to platinum-based chemotherapy is the major barrier to treating epithelial ovarian cancer. To improve patient outcomes, it is critical to identify the underlying mechanisms that promote platinum resistance. Emerging evidence supports the concept that platinum-based therapies are able to eliminate the bulk of differentiated cancer cells, but are unable to eliminate cancer initiating cells (CIC). To date, the relevant pathways that regulate ovarian CICs remain elusive. Several correlative studies have shown that Wnt/β-catenin pathway activation is associated with poor outcomes in patients with high-grade serous ovarian cancer (HGSOC). However, the functional relevance of these findings remain to be delineated. We have uncovered that Wnt/β-catenin pathway activation is a critical driver of HGSOC chemotherapy resistance, and targeted inhibition of this pathway, which eliminates CICs, represents a novel and effective treatment for chemoresistant HGSOC. Here we show that Wnt/β-catenin signaling is activated in ovarian CICs, and targeted inhibition of β-catenin potently sensitized cells to cisplatin and decreased CIC tumor sphere formation. Furthermore, the Wnt/β-catenin specific inhibitor iCG-001 potently sensitized cells to cisplatin and decreased stem-cell frequency in platinum resistant cells. Taken together, our data is the first report providing evidence that the Wnt/β-catenin signaling pathway maintains stem-like properties and drug resistance of primary HGSOC PDX derived platinum resistant models, and therapeutic targeting of this pathway with iCG-001/PRI-724, which has been shown to be well tolerated in Phase I trials, may be an effective treatment option. Impact Journals LLC 2015-06-29 /pmc/articles/PMC4695147/ /pubmed/26125441 Text en Copyright: © 2015 Nagaraj et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Nagaraj, Anil Belur Joseph, Peronne Kovalenko, Olga Singh, Sareena Armstrong, Amy Redline, Raymond Resnick, Kimberly Zanotti, Kristine Waggoner, Steven DiFeo, Analisa Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance |
title | Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance |
title_full | Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance |
title_fullStr | Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance |
title_full_unstemmed | Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance |
title_short | Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance |
title_sort | critical role of wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695147/ https://www.ncbi.nlm.nih.gov/pubmed/26125441 |
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