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Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy
Platinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. However, resistance remains a primary issue. Our findings point to the possibility of exploiting levels of cell divis...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163776/ https://www.ncbi.nlm.nih.gov/pubmed/34050247 http://dx.doi.org/10.1038/s42003-021-02136-8 |
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author | Kildey, Katrina Gandhi, Neha S. Sahin, Katherine B. Shah, Esha T. Boittier, Eric Duijf, Pascal H. G. Molloy, Christopher Burgess, Joshua T. Beard, Sam Bolderson, Emma Suraweera, Amila Richard, Derek J. O’Byrne, Kenneth J. Adams, Mark N. |
author_facet | Kildey, Katrina Gandhi, Neha S. Sahin, Katherine B. Shah, Esha T. Boittier, Eric Duijf, Pascal H. G. Molloy, Christopher Burgess, Joshua T. Beard, Sam Bolderson, Emma Suraweera, Amila Richard, Derek J. O’Byrne, Kenneth J. Adams, Mark N. |
author_sort | Kildey, Katrina |
collection | PubMed |
description | Platinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. However, resistance remains a primary issue. Our findings point to the possibility of exploiting levels of cell division cycle associated protein-3 (CDCA3) to improve response of NSCLC tumours to therapy. We demonstrate that in patients and in vitro analyses, CDCA3 levels correlate with measures of genome instability and platinum sensitivity, whereby CDCA3(high) tumours are sensitive to cisplatin and carboplatin. In NSCLC, CDCA3 protein levels are regulated by the ubiquitin ligase APC/C and cofactor Cdh1. Here, we identified that the degradation of CDCA3 is modulated by activity of casein kinase 2 (CK2) which promotes an interaction between CDCA3 and Cdh1. Supporting this, pharmacological inhibition of CK2 with CX-4945 disrupts CDCA3 degradation, elevating CDCA3 levels and increasing sensitivity to platinum agents. We propose that combining CK2 inhibitors with platinum-based chemotherapy could enhance platinum efficacy in CDCA3(low) NSCLC tumours and benefit patients. |
format | Online Article Text |
id | pubmed-8163776 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81637762021-06-10 Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy Kildey, Katrina Gandhi, Neha S. Sahin, Katherine B. Shah, Esha T. Boittier, Eric Duijf, Pascal H. G. Molloy, Christopher Burgess, Joshua T. Beard, Sam Bolderson, Emma Suraweera, Amila Richard, Derek J. O’Byrne, Kenneth J. Adams, Mark N. Commun Biol Article Platinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. However, resistance remains a primary issue. Our findings point to the possibility of exploiting levels of cell division cycle associated protein-3 (CDCA3) to improve response of NSCLC tumours to therapy. We demonstrate that in patients and in vitro analyses, CDCA3 levels correlate with measures of genome instability and platinum sensitivity, whereby CDCA3(high) tumours are sensitive to cisplatin and carboplatin. In NSCLC, CDCA3 protein levels are regulated by the ubiquitin ligase APC/C and cofactor Cdh1. Here, we identified that the degradation of CDCA3 is modulated by activity of casein kinase 2 (CK2) which promotes an interaction between CDCA3 and Cdh1. Supporting this, pharmacological inhibition of CK2 with CX-4945 disrupts CDCA3 degradation, elevating CDCA3 levels and increasing sensitivity to platinum agents. We propose that combining CK2 inhibitors with platinum-based chemotherapy could enhance platinum efficacy in CDCA3(low) NSCLC tumours and benefit patients. Nature Publishing Group UK 2021-05-28 /pmc/articles/PMC8163776/ /pubmed/34050247 http://dx.doi.org/10.1038/s42003-021-02136-8 Text en © The Author(s) 2021 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 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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kildey, Katrina Gandhi, Neha S. Sahin, Katherine B. Shah, Esha T. Boittier, Eric Duijf, Pascal H. G. Molloy, Christopher Burgess, Joshua T. Beard, Sam Bolderson, Emma Suraweera, Amila Richard, Derek J. O’Byrne, Kenneth J. Adams, Mark N. Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy |
title | Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy |
title_full | Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy |
title_fullStr | Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy |
title_full_unstemmed | Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy |
title_short | Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy |
title_sort | elevating cdca3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163776/ https://www.ncbi.nlm.nih.gov/pubmed/34050247 http://dx.doi.org/10.1038/s42003-021-02136-8 |
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