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- 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.
- Authors
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
- Abstract
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.
- Subjects
UNITED States. Food &; Drug Administration; OVARIAN cancer; BREAST cancer; POLY(ADP-ribose) polymerase; TUMOR growth; CYCLIN-dependent kinase inhibitors; CISPLATIN; BREAST
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 5, p2892
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms23052892