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.
Highlights
Breast cancer is the leading cause of cancer morbidity and mortality in women worldwide, accounting for 24.2% of new cancer cases and 15.0% of cancer deaths [1]
Formerly referred to as AZD2281 or KU0059436, was the first PARPi introduced into clinical practice, which was initially approved as a maintenance therapy in platinum-sensitive relapsed ovarian cancer [26] and later approved for treatment of BRCA-mutated (HR-deficiency) breast and ovarian cancers [27–29]
Several studies indicated that a combination of Olaparib with CDK4/6i displayed therapeutic synergy in MYC highly expressed breast and ovarian cancers with homologous recombination (HR) proficiency [22,23], which represents a new treatment paradigm in these cancers beyond HR-deficiency
Summary
Breast cancer is the leading cause of cancer morbidity and mortality in women worldwide, accounting for 24.2% of new cancer cases and 15.0% of cancer deaths [1]. Three PARP inhibitors, Olaparib, Rucaparib, and Niraparib, have been approved by FDA for treatment of breast and ovarian cancers in patients with mutations in BRCA1 and BRCA2, which are key mediators of HR repair, providing the first anti-cancer therapy based on synthetic lethality [16–18]. Therapeutic synergy for combination of PARPi and CDK4/6i has been demonstrated in MYC highly expressed breast and ovarian cancers with HR proficiency [22,23], which provides a new synthetic lethal strategy for treatment of these cancers regardless HR status. Any strategies or compounds that could combine PARP and CDK4/6 inhibition may improve the clinic outcomes and benefit more patients with breast or ovarian cancer. We developed a new compound ZC-22, which can effectively inhibit the activity of both PARP and CDK4/6 and displayed better anti-tumor efficacy than PARPi Olaparib and CDK4/6i Abemaciclib monotherapy, or even combination therapy in both cell and mouse models. We have developed a novel compound that can potentially benefit breast and ovarian cancer patients with primary or secondary HR proficiency as monotherapy or in combination with platinum-based chemotherapy
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