CDK4/6 as a Therapeutic Target in HR+/HER2- Breast Cancer Cells-Current Treatment Status

Abstract

Breast cancer is the most frequently diagnosed neoplasm in the world. It can be classified into four main subtypes, each of them showing differences in the expression of hormone receptor (HR), human epidermal growth factor receptor 2 (HER2), and in cell metabolism. Since 2015, when The U.S. Food and Drug Administration (FDA) approved the first cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that regulates the cell cycle, treatment of HR+/HER2- BC has become much more effective. Currently, palbociclib, ribociclib, and abemaciclib are more often used both in combination with endocrine therapy as well as in monotherapy. Their application has been extensively verified in many clinical trials such as PALOMA-1,2,3, MONALEESA-1,2,3,7, and MONARCH-1,2,3, which allowed the verification of differences in their effectiveness, dosage, and adverse effects. Subsequent studies, MonarchE and NATALEE, examined the role of these inhibitors as adjuvant therapy, as well as at verifying their safety. Moreover, dalpiciclib is being investigated in HR+/HER2- BC treatment. This article will summarize clinical efficacy, recommendations, and differences in toxicity profile between palbociclib, ribociclib, and abemaciclib and will also discuss the possibility of using dalpiciclib in the treatment of breast cancer.

Keywords: CDK4/6 inhibitors; HR+/HER2−; abemaciclib; breast cancer; dalpiciclib; palbociclib; ribociclib.

Figure 1

Simplified diagram of the regulation of the cell cycle (modified on Deptala A. habilitation thesis). Abbreviations: CDK—cyclin-dependent kinase; MDM2—mouse double minute 2 homolog; pRB—retinoblastoma protein; CDC25—cell division cycle phosphatase family; P—phosphorylation.

Figure 2

Simplified diagram of the regulation of the cell cycle including CIP/KIP and INK4 inhibitors (modified on Deptala A. habilitation thesis). Abbreviations: CDK—cyclin-dependent kinase; INK4—family of CDK inhibitors; CIP/KIPs—CDK-interacting proteins/kinase inhibitor proteins; MDM2—mouse double minute 2 homolog; pRB—retinoblastoma protein; CDC25—cell division cycle phosphatase family; P—phosphorylation.

Figure 3

The mechanism of the signalization by HER2 and ER, cyclins, CDK, and other proteins related to cell division. CDK4/6 inhibitors regulating the cell cycle. Own work; based on [31]. Abbreviations: CDK—cyclin-dependent kinase; P—phosphorylation.