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A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer

In recent years, three PARP inhibitors and three CDK4/6 inhibitors have been approved by the FDA for the treatment of recurrent ovarian cancer and advanced ER-positive breast cancer, respectively. However, the clinical benefits of the PARPi or CDK4/6i monotherapy are not as satisfied as expected and...

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Autores principales: Tian, Chenchen, Wei, Yufan, Li, Jianjun, Huang, Zhi, Wang, Qiong, Lin, Yingxue, Lv, Xingping, Chen, Yanan, Fan, Yan, Sun, Peiqing, Xiang, Rong, Chang, Antao, Yang, Shuang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911181/
https://www.ncbi.nlm.nih.gov/pubmed/35270034
http://dx.doi.org/10.3390/ijms23052892
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author Tian, Chenchen
Wei, Yufan
Li, Jianjun
Huang, Zhi
Wang, Qiong
Lin, Yingxue
Lv, Xingping
Chen, Yanan
Fan, Yan
Sun, Peiqing
Xiang, Rong
Chang, Antao
Yang, Shuang
author_facet Tian, Chenchen
Wei, Yufan
Li, Jianjun
Huang, Zhi
Wang, Qiong
Lin, Yingxue
Lv, Xingping
Chen, Yanan
Fan, Yan
Sun, Peiqing
Xiang, Rong
Chang, Antao
Yang, Shuang
author_sort Tian, Chenchen
collection PubMed
description In recent years, three PARP inhibitors and three CDK4/6 inhibitors have been approved by the FDA for the treatment of recurrent ovarian cancer and advanced ER-positive breast cancer, respectively. However, the clinical benefits of the PARPi or CDK4/6i monotherapy are not as satisfied as expected and benefit only a fraction of patients. Current studies have shown therapeutic synergy for combinations of PARPi and CDK4/6i in breast and ovarian cancers with homologous recombination (HR) proficiency, which represents a new synthetic lethal strategy for treatment of these cancers regardless HR status. Thus, any compounds or strategies that can combine PARP and CDK4/6 inhibition will likely have great potential in improving clinic outcomes and in benefiting more patients. In this study, we developed a novel compound, ZC-22, that effectively inhibited both PARP and CDK4/6. This dual-targeting compound significantly inhibited breast and ovarian cancer cells by inducing cell cycle arrest and severe DNA damage both in vitro and in vivo. Interestingly, the efficacy of ZC-22 is even higher than the combination of PARPi Olaparib and CDK4/6i Abemaciclib in most breast and ovarian cancer cells, suggesting that it may be an effective alternative for the PARPi and CDK4/6i combination therapy. Moreover, ZC-22 sensitized breast and ovarian cancer cells to cisplatin treatment, a widely used chemotherapeutic agent. Altogether, our study has demonstrated the potency of a novel CDK4/6 and PARP dual inhibitor, which can potentially be developed into a monotherapy or combinatorial therapy with cisplatin for breast and ovarian cancer patients with HR proficiency.
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spelling pubmed-89111812022-03-11 A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer Tian, Chenchen Wei, Yufan Li, Jianjun Huang, Zhi Wang, Qiong Lin, Yingxue Lv, Xingping Chen, Yanan Fan, Yan Sun, Peiqing Xiang, Rong Chang, Antao Yang, Shuang Int J Mol Sci Article In recent years, three PARP inhibitors and three CDK4/6 inhibitors have been approved by the FDA for the treatment of recurrent ovarian cancer and advanced ER-positive breast cancer, respectively. However, the clinical benefits of the PARPi or CDK4/6i monotherapy are not as satisfied as expected and benefit only a fraction of patients. Current studies have shown therapeutic synergy for combinations of PARPi and CDK4/6i in breast and ovarian cancers with homologous recombination (HR) proficiency, which represents a new synthetic lethal strategy for treatment of these cancers regardless HR status. Thus, any compounds or strategies that can combine PARP and CDK4/6 inhibition will likely have great potential in improving clinic outcomes and in benefiting more patients. In this study, we developed a novel compound, ZC-22, that effectively inhibited both PARP and CDK4/6. This dual-targeting compound significantly inhibited breast and ovarian cancer cells by inducing cell cycle arrest and severe DNA damage both in vitro and in vivo. Interestingly, the efficacy of ZC-22 is even higher than the combination of PARPi Olaparib and CDK4/6i Abemaciclib in most breast and ovarian cancer cells, suggesting that it may be an effective alternative for the PARPi and CDK4/6i combination therapy. Moreover, ZC-22 sensitized breast and ovarian cancer cells to cisplatin treatment, a widely used chemotherapeutic agent. Altogether, our study has demonstrated the potency of a novel CDK4/6 and PARP dual inhibitor, which can potentially be developed into a monotherapy or combinatorial therapy with cisplatin for breast and ovarian cancer patients with HR proficiency. MDPI 2022-03-07 /pmc/articles/PMC8911181/ /pubmed/35270034 http://dx.doi.org/10.3390/ijms23052892 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tian, Chenchen
Wei, Yufan
Li, Jianjun
Huang, Zhi
Wang, Qiong
Lin, Yingxue
Lv, Xingping
Chen, Yanan
Fan, Yan
Sun, Peiqing
Xiang, Rong
Chang, Antao
Yang, Shuang
A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer
title A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer
title_full A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer
title_fullStr A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer
title_full_unstemmed A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer
title_short A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer
title_sort novel cdk4/6 and parp dual inhibitor zc-22 effectively suppresses tumor growth and improves the response to cisplatin treatment in breast and ovarian cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911181/
https://www.ncbi.nlm.nih.gov/pubmed/35270034
http://dx.doi.org/10.3390/ijms23052892
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