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Review
. 2023 Oct 11:15:17588359231205848.
doi: 10.1177/17588359231205848. eCollection 2023.

CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity - a narrative review

Dragica Pavlovic  1 , Danijela Niciforovic  2 , Dragana Papic  3 , Katarina Milojevic  2 , Marina Markovic  2   4
Affiliations
Review

CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity - a narrative review

Dragica Pavlovic et al. Ther Adv Med Oncol. .

Abstract

Breast cancer is characterized by the uncontrolled proliferation of breast cells, with a high incidence reported in 2020 to have affected over 2 million women. In recent years, the conventional methods of treating breast cancer have involved radiotherapy and chemotherapy. However, the emergence of CDK4/6 inhibitors has shown potential as a promising cancer therapy. Cyclin-dependent kinases (CDK) inhibitors are a class of molecules that impede the formation of an active kinase complex, thereby hindering its activity and consequently halting the progression of the cell cycle. It was discovered that they have a significant impact on impeding the progression of the cancer. This is evident with the Food and Drug Administration's approval of drugs such as palbociclib, ribociclib, and abemaciclib for hormone receptor-positive metastatic breast cancer in combination with specific endocrine therapies. In spite of enormous success in breast cancer treatment, certain obstacles have emerged, such as therapy resistance, side effects, and most of all, cardiotoxicity. Some of these drawbacks have been successfully overcome by dosage reduction, different combinations of the drugs, and the assessment of each patient's condition and suitability prior to treatment. Yet other drawbacks still require tenacious research, especially certain cases of cardiotoxicities. This article delves into the biological mechanisms of CDK4/6 in the cell cycle and cancer, as well as the clinical advantages and most common adverse events (AEs) associated with CDK4/6 inhibitors. The primary objective of this review is to provide a comprehensive analysis of cardiotoxic AEs and elucidate the underlying pathophysiological mechanisms responsible for the cardiotoxicity of CDK4/6 inhibitors.

Keywords: CDK4/6 inhibitors; adverse events; breast cancer; cardiotoxicity; therapy.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.
Mechanism of action of CDK4/6 inhibitors in cell cycle and cancer. This diagram illustrates the cell cycle, a process that leads to cell division. As depicted by the circular dotted arrow in this diagram, normal cell replication progresses from the G1 (first growth period) to the S (DNA replication), G2 (second growth period), and M (mitosis period) phases. A number of proteins, including CDKs, regulate this process. CDK 4/6 forms a complex with cyclin D, which phosphorylates the tumor suppressor protein retinoblastoma protein (Rb) and results in its inactivation (thin arrow in figure). Ultimately, this permits the progression from G1 to S in the cell cycle. CDK 4/6 inhibitors block the formation of the CDK 4/6-cyclin D1 complex and the phosphorylation of Rb to arrest the cell cycle. The uncontrolled proliferation observed in cancer is initiated by the dysregulation of restriction points (depicted with thick black arrows in figure). CDKs, cyclin-dependent kinases; DNA, deoxyribonucleic acid; Rb, retinoblastoma protein.
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