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Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells in a cell line model
BACKGROUND: CDK4/6 inhibitors such as ribociclib are becoming widely used targeted therapies in hormone-receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) breast cancer. However, cancers can advance due to drug resistance, a problem in which tumor heterogeneity and evo...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301982/ https://www.ncbi.nlm.nih.gov/pubmed/32565737 http://dx.doi.org/10.1186/s12935-020-01337-1 |
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author | Grolmusz, Vince Kornél Chen, Jinfeng Emond, Rena Cosgrove, Patrick A. Pflieger, Lance Nath, Aritro Moos, Philip J. Bild, Andrea H. |
author_facet | Grolmusz, Vince Kornél Chen, Jinfeng Emond, Rena Cosgrove, Patrick A. Pflieger, Lance Nath, Aritro Moos, Philip J. Bild, Andrea H. |
author_sort | Grolmusz, Vince Kornél |
collection | PubMed |
description | BACKGROUND: CDK4/6 inhibitors such as ribociclib are becoming widely used targeted therapies in hormone-receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) breast cancer. However, cancers can advance due to drug resistance, a problem in which tumor heterogeneity and evolution are key features. METHODS: Ribociclib-resistant HR+/HER2− CAMA-1 breast cancer cells were generated through long-term ribociclib treatment. Characterization of sensitive and resistant cells were performed using RNA sequencing and whole exome sequencing. Lentiviral labeling with different fluorescent proteins enabled us to track the proliferation of sensitive and resistant cells under different treatments in a heterogeneous, 3D spheroid coculture system using imaging microscopy and flow cytometry. RESULTS: Transcriptional profiling of sensitive and resistant cells revealed the downregulation of the G2/M checkpoint in the resistant cells. Exploiting this acquired vulnerability; resistant cells exhibited collateral sensitivity for the Wee-1 inhibitor, adavosertib (AZD1775). The combination of ribociclib and adavosertib achieved additional antiproliferative effect exclusively in the cocultures compared to monocultures, while decreasing the selection for resistant cells. CONCLUSIONS: Our results suggest that optimal antiproliferative effects in heterogeneous cancers can be achieved via an integrative therapeutic approach targeting sensitive and resistant cancer cell populations within a tumor, respectively. |
format | Online Article Text |
id | pubmed-7301982 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-73019822020-06-19 Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells in a cell line model Grolmusz, Vince Kornél Chen, Jinfeng Emond, Rena Cosgrove, Patrick A. Pflieger, Lance Nath, Aritro Moos, Philip J. Bild, Andrea H. Cancer Cell Int Primary Research BACKGROUND: CDK4/6 inhibitors such as ribociclib are becoming widely used targeted therapies in hormone-receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) breast cancer. However, cancers can advance due to drug resistance, a problem in which tumor heterogeneity and evolution are key features. METHODS: Ribociclib-resistant HR+/HER2− CAMA-1 breast cancer cells were generated through long-term ribociclib treatment. Characterization of sensitive and resistant cells were performed using RNA sequencing and whole exome sequencing. Lentiviral labeling with different fluorescent proteins enabled us to track the proliferation of sensitive and resistant cells under different treatments in a heterogeneous, 3D spheroid coculture system using imaging microscopy and flow cytometry. RESULTS: Transcriptional profiling of sensitive and resistant cells revealed the downregulation of the G2/M checkpoint in the resistant cells. Exploiting this acquired vulnerability; resistant cells exhibited collateral sensitivity for the Wee-1 inhibitor, adavosertib (AZD1775). The combination of ribociclib and adavosertib achieved additional antiproliferative effect exclusively in the cocultures compared to monocultures, while decreasing the selection for resistant cells. CONCLUSIONS: Our results suggest that optimal antiproliferative effects in heterogeneous cancers can be achieved via an integrative therapeutic approach targeting sensitive and resistant cancer cell populations within a tumor, respectively. BioMed Central 2020-06-17 /pmc/articles/PMC7301982/ /pubmed/32565737 http://dx.doi.org/10.1186/s12935-020-01337-1 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 | Primary Research Grolmusz, Vince Kornél Chen, Jinfeng Emond, Rena Cosgrove, Patrick A. Pflieger, Lance Nath, Aritro Moos, Philip J. Bild, Andrea H. Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells in a cell line model |
title | Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells in a cell line model |
title_full | Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells in a cell line model |
title_fullStr | Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells in a cell line model |
title_full_unstemmed | Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells in a cell line model |
title_short | Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells in a cell line model |
title_sort | exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells in a cell line model |
topic | Primary Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301982/ https://www.ncbi.nlm.nih.gov/pubmed/32565737 http://dx.doi.org/10.1186/s12935-020-01337-1 |
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