Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives

Dall'Acqua, Alessandra; Bartoletti, Michele; Masoudi-Khoram, Nastaran; Sorio, Roberto; Puglisi, Fabio; Belletti, Barbara; Baldassarre, Gustavo

doi:10.3390/cancers13123035

Cited by 14 publications

(14 citation statements)

References 106 publications

(116 reference statements)

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“…Combination of CDK-i with conventional chemotherapeutic drugs has been long debated, due to the fact that cell cycle arrest induced by CDK-i seems in clear conflict with the aim of conventional chemotherapy, which is the targeting of proliferating cells ( 81 ).…”

Section: Cdk-i and Conventional Chemotherapymentioning

confidence: 99%

CDK4/6 Inhibitors in Combination Therapies: Better in Company Than Alone: A Mini Review

et al. 2022

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The cyclin D-CDK4/6 complexes play a pivotal role in controlling the cell cycle. Deregulation in cyclin D-CDK4/6 pathway has been described in many types of cancer and it invariably leads to uncontrolled cell proliferation. Many efforts have been made to develop a target therapy able to inhibit CDK4/6 activity. To date, three selective CDK4/6 small inhibitors have been introduced in the clinic for the treatment of hormone positive advanced breast cancer patients, following the impressive results obtained in phase III clinical trials. However, since their approval, clinical evidences have demonstrated that about 30% of breast cancer is intrinsically resistant to CDK4/6 inhibitors and that prolonged treatment eventually leads to acquired resistance in many patients. So, on one hand, clinical and preclinical studies fully support to go beyond breast cancer and expand the use of CDK4/6 inhibitors in other tumor types; on the other hand, the question of primary and secondary resistance has to be taken into account, since it is now very clear that neoplastic cells rapidly develop adaptive strategies under treatment, eventually resulting in disease progression. Resistance mechanisms so far discovered involve both cell-cycle and non-cell-cycle related escape strategies. Full understanding is yet to be achieved but many different pathways that, if targeted, may lead to reversion of the resistant phenotype, have been already elucidated. Here, we aim to summarize the knowledge in this field, focusing on predictive biomarkers, to recognize intrinsically resistant tumors, and therapeutic strategies, to overcome acquired resistance.

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Section: Cdk-i and Conventional Chemotherapymentioning

confidence: 99%

CDK4/6 Inhibitors in Combination Therapies: Better in Company Than Alone: A Mini Review

et al. 2022

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“…Numerous clinical trials are ongoing to assess CDK4/6i in combination therapy to treat breast and additional cancer types. However, little information of CDK4/6i in ovarian cancer treatment has been reported yet, though substantial interests prompt ongoing efforts to evaluate a potential role in ovarian cancer treatment ( 83 , 84 ).…”

Section: Clinical Efficacy Of Cdk4/6 Inhibitionmentioning

confidence: 99%

“…The utility of CDK4/6 inhibition as a component in a combined therapy regimen with additional agent(s) is an area of active investigation as CDK4/6i by itself lacks sufficient activity ( 81 , 84 , 86 ). One potential mechanism of synergy is that both inhibition of the mitogenic signaling pathway that regulates D-type cyclins, and blocking of CDK4/6 activities, are necessary for a synergized therapy to prevent tumor cell proliferation ( 81 ).…”

Section: Combination Therapy: Rationale For Synergy Between Paclitaxe...mentioning

confidence: 99%

Rationale for combination of paclitaxel and CDK4/6 inhibitor in ovarian cancer therapy — non-mitotic mechanisms of paclitaxel

et al. 2022

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Taxanes and CDK4/6 inhibitors (CDK4/6i) are two families of successful anti-mitotic drugs used in the treatment of solid tumors. Paclitaxel, representing taxane compounds, has been used either alone or in combination with other agents (commonly carboplatin/cisplatin) in the treatment of many solid tumors including ovarian, breast, lung, prostate cancers, and Kaposi’s sarcoma. Paclitaxel has been routinely prescribed in cancer treatment since the 1990s, and its prominent role is unlikely to be replaced in the foreseeable future. Paclitaxel and other taxanes work by binding to and stabilizing microtubules, causing mitotic arrest, aberrant mitosis, and cell death. CDK4/6i (palbociclib, ribociclib, abemaciclib) are relatively new cell cycle inhibitors that have been found to be effective in breast cancer treatment, and are currently being developed in other solid tumors. CDK4/6i blocks cell cycle progression at the G1 phase, resulting in cell death by mechanisms not yet fully elucidated. At first glance, paclitaxel and CDK4/6i are unlikely synergistic agents as both are cell cycle inhibitors that work at different phases of the cell cycle, and few clinical trials have yet considered adding CDK4/6i to existing paclitaxel chemotherapy. However, recent findings suggest the importance of a non-mitotic mechanism of paclitaxel in cancer cell death and pre-clinical data support rationale for a strategic paclitaxel and CDK4/6i combination. In mouse tumor model studies, drug sequencing resulted in differential efficacy, indicating complex biological interactions of the two drugs. This article reviews the rationales of combining paclitaxel with CDK4/6i as a potential therapeutic option in recurrent ovarian cancer.

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“…To date, three highly selective CDK4/6i, Palbociclib (PD0332991), Ribociclib (LEE0011), and Abemaciclib (LY2835219), have been approved by FDA as first-line therapy for the treatment of hormone receptor-positive (HR + ) and human epidermal growth factor receptor 2-negative (HER2 − ) metastatic breast cancer in combination with endocrine therapy [ 7 , 8 , 9 , 10 ]. Recently, CDK4/6i have shown potent antitumor activity in ovarian cancer either as single agent or in combination with platinum-based chemotherapy in several clinical trials [ 9 , 11 , 12 ]. However, the clinical benefits of CDK4/6i are limited and were only observed in a fraction of breast and ovarian cancer patients [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, CDK4/6i have shown potent antitumor activity in ovarian cancer either as single agent or in combination with platinum-based chemotherapy in several clinical trials [ 9 , 11 , 12 ]. However, the clinical benefits of CDK4/6i are limited and were only observed in a fraction of breast and ovarian cancer patients [ 12 , 13 ]. The combination of CDK4/6 inhibitors with other agents might be a more effective strategy to improve clinical outcomes and to extend the use of CDK4/6 inhibitors to a broader spectrum of breast and ovarian cancer patients than CDK4/6i alone.…”

Section: Introductionmentioning

confidence: 99%

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

Wei

et al. 2022

IJMS

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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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Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives

Cited by 14 publications

References 106 publications

CDK4/6 Inhibitors in Combination Therapies: Better in Company Than Alone: A Mini Review

CDK4/6 Inhibitors in Combination Therapies: Better in Company Than Alone: A Mini Review

Rationale for combination of paclitaxel and CDK4/6 inhibitor in ovarian cancer therapy — non-mitotic mechanisms of paclitaxel

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

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