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

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.

Targeting the stimulator of interferon genes (STING) in breast cancer

“…Therefore, inhibiting DNA repair and promoting DDR progression, which activates the cGAS-STING pathway, represents a promising avenue for cancer therapy. Other drugs, such as PARP1 inhibitors, have already gained approval for treating breast and ovarian cancers, demonstrating remarkable efficacy ( Staniszewska et al, 2022 ; Tian et al, 2022 ). Similarly, inhibitors targeting DDR-related genes, such as DNA-dependent protein kinase, catalytic subunit, ATM, ataxia telangiectasia and Rad3-related protein, CHK1, and WEE1, exhibit promising anti-cancer effects ( Wengner et al, 2020 ).…”

Molecular Research and Treatment of Breast Cancer

“…One such compound, ZC-22, inhibited breast cancer cell proliferation through DNA damage induction and cell cycle arrest. ZC-22 exhibited higher activity than the combination of PARPi olaparib and CDK4/6i abemaciclib and sensitized breast cancer cells to the activity of cisplatin, indicating its potential application in mono- and combination therapy [ 13 ].…”