# Efficacy and Mechanisms of CDK4/6 Inhibitors in Breast Cancer: Advancing Targeted Therapeutic Strategies

## TL;DR

CDK4/6 inhibitors are effective in treating certain breast cancers, but challenges like resistance and side effects remain, requiring further research and combination therapies.

## Contribution

This review synthesizes current evidence on CDK4/6 inhibitors, focusing on their mechanisms, resistance, and personalized therapy strategies in HR+/HER2− breast cancer.

## Key findings

- CDK4/6 inhibitors combined with endocrine therapy improve progression-free survival in HR+/HER2− breast cancer.
- Resistance mechanisms limit long-term efficacy, necessitating combination strategies with other targeted medicines.
- Next-generation CDK inhibitors and adaptive trials may expand their use beyond breast cancer.

## Abstract

Breast cancer remains the primary cause of cancer-related mortality for women globally; therefore, further breakthroughs in treatment approaches are crucial. Palbociclib, ribociclib, and abemaciclib are among the Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors that have become an innovative family of targeted therapy for hormone receptor-positive, Human Epidermal Growth factor receptor 2 (HR+/HER2−) breast cancer. These inhibitors work by preventing the action of CDK4/6, which are crucial in the regulation of the cell cycle. Leading cancer cells to cell cycle arrest and undergo apoptosis. When these inhibitors are used with endocrine medicines like letrozole and fulvestrant, clinical trials lead positive impact in progression-free survival and, in a few cases, complete survival. However, despite their effectiveness, resistance mechanisms are primary and current acquired problems, requiring combined approaches with additional targeted medicines and continuous investigation into innovative therapeutic plans. To maintain patient compliance and quality of life, common side effects such as tiredness, gastrointestinal problems, and neutropenia need to be effectively managed. There is hopefulness for wider oncological applications as next-generation CDK inhibitor development and adaptive clinical trials continue to test their potential beyond breast cancer. CDK4/6 inhibitors continue to be a key part of breast cancer treatment as cancer biology advances, marking a major advancement towards more potent and customized cancer medicines. This review aims to provide current evidence on CDK4/6 inhibitors in HR+/HER2− breast cancer, highlighting their mechanisms, interaction with endocrine resistance, combination strategies, and emerging biomarkers guiding personalized therapy.