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Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer

Basal-like breast cancer is an incurable disease with limited therapeutic options, mainly due to the frequent development of anti-cancer drug resistance. Therefore, identification of druggable targets to improve current therapies and overcome these resistances is a major goal. Targeting DNA repair m...

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Autores principales: Nieto-Jimenez, Cristina, Alcaraz-Sanabria, Ana, Martinez-Canales, Sandra, Corrales-Sanchez, Veronica, Montero, Juan Carlos, Burgos, Miguel, Nuncia-Cantarero, Miriam, Pandiella, Atanasio, Galan-Moya, Eva M., Ocaña, Alberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730833/
https://www.ncbi.nlm.nih.gov/pubmed/33261142
http://dx.doi.org/10.3390/ijms21239034
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author Nieto-Jimenez, Cristina
Alcaraz-Sanabria, Ana
Martinez-Canales, Sandra
Corrales-Sanchez, Veronica
Montero, Juan Carlos
Burgos, Miguel
Nuncia-Cantarero, Miriam
Pandiella, Atanasio
Galan-Moya, Eva M.
Ocaña, Alberto
author_facet Nieto-Jimenez, Cristina
Alcaraz-Sanabria, Ana
Martinez-Canales, Sandra
Corrales-Sanchez, Veronica
Montero, Juan Carlos
Burgos, Miguel
Nuncia-Cantarero, Miriam
Pandiella, Atanasio
Galan-Moya, Eva M.
Ocaña, Alberto
author_sort Nieto-Jimenez, Cristina
collection PubMed
description Basal-like breast cancer is an incurable disease with limited therapeutic options, mainly due to the frequent development of anti-cancer drug resistance. Therefore, identification of druggable targets to improve current therapies and overcome these resistances is a major goal. Targeting DNA repair mechanisms has reached the clinical setting and several strategies, like the inhibition of the CHK1 kinase, are currently in clinical development. Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. We identified a synergistic action of these inhibitors with agents that produce DNA damage, like platinum compounds, gemcitabine, and the PARP inhibitor olaparib. Our results demonstrated that the combination of rabusertib with these chemotherapies also has a synergistic impact on tumor initiation, invasion capabilities, and apoptosis in vitro. We also revealed a biochemical effect on DNA damage and caspase-dependent apoptosis pathways through the phosphorylation of H2AX, the degradation of full-length PARP, and the increase of caspases 3 and 8 activity. This agent also demonstrated synergistic activity in a platinum-resistant cell line, inducing an increase in cell death in response to cisplatin only when combined with rabusertib, while no toxic effect was found on non-tumorigenic breast tissue-derived cell lines. Lastly, the combination of CHK1 inhibitor with cisplatin and gemcitabine resulted in more activity than single or double combinations, leading to a higher apoptotic effect. In conclusion, in our study we identify therapeutic options for the clinical development of CHK1 inhibitors, and confirm that the inhibition of this kinase can overcome acquired resistance to cisplatin.
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spelling pubmed-77308332020-12-12 Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer Nieto-Jimenez, Cristina Alcaraz-Sanabria, Ana Martinez-Canales, Sandra Corrales-Sanchez, Veronica Montero, Juan Carlos Burgos, Miguel Nuncia-Cantarero, Miriam Pandiella, Atanasio Galan-Moya, Eva M. Ocaña, Alberto Int J Mol Sci Article Basal-like breast cancer is an incurable disease with limited therapeutic options, mainly due to the frequent development of anti-cancer drug resistance. Therefore, identification of druggable targets to improve current therapies and overcome these resistances is a major goal. Targeting DNA repair mechanisms has reached the clinical setting and several strategies, like the inhibition of the CHK1 kinase, are currently in clinical development. Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. We identified a synergistic action of these inhibitors with agents that produce DNA damage, like platinum compounds, gemcitabine, and the PARP inhibitor olaparib. Our results demonstrated that the combination of rabusertib with these chemotherapies also has a synergistic impact on tumor initiation, invasion capabilities, and apoptosis in vitro. We also revealed a biochemical effect on DNA damage and caspase-dependent apoptosis pathways through the phosphorylation of H2AX, the degradation of full-length PARP, and the increase of caspases 3 and 8 activity. This agent also demonstrated synergistic activity in a platinum-resistant cell line, inducing an increase in cell death in response to cisplatin only when combined with rabusertib, while no toxic effect was found on non-tumorigenic breast tissue-derived cell lines. Lastly, the combination of CHK1 inhibitor with cisplatin and gemcitabine resulted in more activity than single or double combinations, leading to a higher apoptotic effect. In conclusion, in our study we identify therapeutic options for the clinical development of CHK1 inhibitors, and confirm that the inhibition of this kinase can overcome acquired resistance to cisplatin. MDPI 2020-11-27 /pmc/articles/PMC7730833/ /pubmed/33261142 http://dx.doi.org/10.3390/ijms21239034 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nieto-Jimenez, Cristina
Alcaraz-Sanabria, Ana
Martinez-Canales, Sandra
Corrales-Sanchez, Veronica
Montero, Juan Carlos
Burgos, Miguel
Nuncia-Cantarero, Miriam
Pandiella, Atanasio
Galan-Moya, Eva M.
Ocaña, Alberto
Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer
title Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer
title_full Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer
title_fullStr Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer
title_full_unstemmed Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer
title_short Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer
title_sort checkpoint kinase 1 pharmacological inhibition synergizes with dna-damaging agents and overcomes platinum resistance in basal-like breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730833/
https://www.ncbi.nlm.nih.gov/pubmed/33261142
http://dx.doi.org/10.3390/ijms21239034
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