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

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

doi:10.3390/cancers13123035

Abstract

Simple SummaryAltered regulation of the cell cycle is a hallmark of cancer. The recent clinical success of the inhibitors of CDK4 and CDK6 has convincingly demonstrated that targeting cell cycle components may represent an effective anti-cancer strategy, at least in some cancer types. However, possible applications of CDK4/6 inhibitors in patients with ovarian cancer is still under evaluation. Here, we describe the possible biological role of CDK4 and CDK6 complexes in ovarian cancer and provide the rationale for the use of CDK4/6 inhibitors in this pathology, alone or in combination with other drugs. This review, coupling basic, preclinical and clinical research studies, could be of great translational value for investigators attempting to design new clinical trials for the better management of ovarian cancer patients.Alterations in components of the cell-cycle machinery are present in essentially all tumor types. In particular, molecular alterations resulting in dysregulation of the G1 to S phase transition have been observed in almost all human tumors, including ovarian cancer. These alterations have been identified as potential therapeutic targets in several cancer types, thereby stimulating the development of small molecule inhibitors of the cyclin dependent kinases. Among these, CDK4 and CDK6 inhibitors confirmed in clinical trials that CDKs might indeed represent valid therapeutic targets in, at least some, types of cancer. CDK4 and CDK6 inhibitors are now used in clinic for the treatment of patients with estrogen receptor positive metastatic breast cancer and their clinical use is being tested in many other cancer types, alone or in combination with other agents. Here, we review the role of CDK4 and CDK6 complexes in ovarian cancer and propose the possible use of their inhibitors in the treatment of ovarian cancer patients with different types and stages of disease.

Highlights

In 2000, Hanahan and Weinberg, by putting together the principal advancements of cancer research during the previous 25 years, provided the scientific community with the knowledge of what, at that time, were the hallmarks of cancer [1]
Watt and colleagues observed that breast cancer cell lines and PDX models treated with the CDK4/6i abemaciclib or palbociclib, displayed a remodeling of the chromatin architecture with a wide activation of transcription enhancers and super-enhancers
Considering these data as whole, we found that a significant fraction of ovarian cancers that have been analyzed display an aberrant expression of cyclins, cyclin dependent kinases (CDK) and/or CDK inhibitors (CDKI) (Table 2), supporting the hypothesis that these tumors could be potentially sensitive to CDK4/6i

Summary

Introduction

In 2000, Hanahan and Weinberg, by putting together the principal advancements of cancer research during the previous 25 years, provided the scientific community with the knowledge of what, at that time, were the hallmarks of cancer [1]. The sustained proliferative signaling and the evasion from growth suppression were and remained two of the most typical traits reported in virtually all cancer cells. Both these features are tightly related to an altered regulation of the cell cycle progression. We will highlight how they have been used so far for the treatment of this disease and what are the future steps that need to be made to possibly expand their success

The Role of CDK4 and CDK6 in the Control of Cell Cycle Progression

Non-Cell Cycle Dependent Activities of CDK4 and CDK6

Expression of CDK4 and CDK6 Containing Complexes in Ovarian Cancer

Findings

10. Conclusions and Future Perspectives