The Evolving Pathways of the Efficacy of and Resistance to CDK4/6 Inhibitors in Breast Cancer

SIMPLE SUMMARY: Nowadays, the upfront treatment for patients facing a diagnosis of advanced luminal breast cancer (BC) is a combination of endocrine therapy (ET) with an inhibitor of CDK4/6 (CDK4/6i), which effectively targets and prevents cell cycle progression in hormone-dependent BC. However, the identification of companion predictive biomarkers and ways to overcome or delay the almost inevitable acquired resistance would increase the clinical benefit of this treatment. In this review, we discuss the state-of-the-art evidence about the efficacy of and resistance to CDK4/6i, pinpointing the most relevant past, present and emerging preclinical and clinical efforts. ABSTRACT: The approval of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has remarkably improved the survival outcomes of patients with advanced hormone receptor-positive (HR+) breast cancer (BC), becoming the new standard of care treatment in these patients. Despite the efficacy of this therapeutic combination, intrinsic and acquired resistance inevitably occurs and represents a major clinical challenge. Several mechanisms associated with resistance to CDK4/6i have been identified, including both cell cycle-related and cell cycle-nonspecific mechanisms. This review discusses new insights underlying the mechanisms of action of CDK4/6i, which are more far-reaching than initially thought, and the currently available evidence of the mechanisms of resistance to CDK4/6i in BC. Finally, it highlights possible treatment strategies to improve CDK4/6i efficacy, summarizing the most relevant clinical data on novel combination therapies involving CDK4/6i.