Role of Senescence Induced by CDK4/6 Inhibitor Palbociclib in Breast Cancer Treatment Response

Abstract

Breast cancer is the most common cancer in women globally and a leading cause of cancer-related deaths. Despite advances in early detection and targeted therapy, the 5-year survival rate drops below 25% when the cancer spreads to nearby tissues or distant organs. Breast cancer is classified into molecular subtypes, with luminal subtypes (ER/PR-positive) being the most prevalent. Luminal B tumors, which may or may not express HER2, are often treated with endocrine therapy (ET), targeting the estrogen receptor. However, resistance to ET is common, and combining ET with CDK4/6 inhibitors, like Palbociclib, has shown to improve progression-free survival. Despite this, nearly all patients experience relapse after 2-3 years of treatment. CDK4/6 inhibitors induce cell cycle arrest, leading to quiescence, which can eventually progress to senescence. Senescent cells exhibit metabolic and phenotypic changes that enable them to resist apoptosis, and there is emerging evidence suggesting that these cells may escape senescence upon treatment withdrawal, regenerating the tumor. This study investigated the effects of long-term senescence induced by Palbociclib in breast cancer cells. After several months of treatment, cells reached 100% senescence, but upon drug withdrawal, some cells resumed proliferation. Protein expression analysis revealed changes linked to resistance mechanisms, including altered levels of HER2 and CDK4/6 inhibitors. These findings suggest that the escape from senescence may contribute to breast cancer relapse after treatment withdrawal.