CDK4/6 inhibitors for the treatment of breast cancer

Cyclin-dependent kinases (CDK)4/6 inhibitors have revolutionized the treatment of hormone receptor-positive (HR+) BC by targeting cell-cycle regulation. These inhibitors of CDK4/6, including palbociclib, ribociclib, and abemaciclib, effectively halt cell-cycle progression at the transition phase of G1 and S, providing significant therapeutic benefits. However, challenges such as resistance and variable patient responses highlight the need for a deeper understanding of biomarkers and resistance mechanisms. Biomarkers like estrogen receptor expression and retinoblastoma protein (RB) status are critical for predicting response, while resistance mechanisms, including RB loss, cyclin E1 upregulation, PI3K/AKT/mTOR pathway activation, and limit long-term efficacy. Emerging research focuses on overcoming these challenges through next-generation inhibitors and combination therapies, including the uses of CDK4/6 inhibitors in TNBC and in combination with immunotherapy. These advancements offer hope for expanding the CDK4/6 inhibitors’ therapeutic potential across diverse breast and other cancer subtypes, ultimately improving patient outcomes through more personalized treatment approaches.