The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance

SIMPLE SUMMARY: Cyclin-dependent kinase inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)), targeting aberrant cell-cycle activity have been evaluated extensively in clinical trials. Significant delays in progression free survival and overall survival are now documented with each agent in estrogen receptor positive and human epidermal growth factor receptor two negative advanced breast cancer including luminal B breast cancer. Therapy resistance, driven by chromosomal instability, results in genomic rearrangements, activation of cell-cycle components (cyclin E/cdk2 in Rb(−) tumors, cyclin D1 in growth factor activated pathways), and the immune response. Molecular analysis of therapy resistant tumors may provide the rational basis for new therapies (brivanib, CYC065, WEE1 kinase and other inhibitors). Luminal B breast cancer is enriched for cyclin D1 overexpression and the chromosomal instability gene signature. The molecular mechanisms governing chromosomal instability in luminal B breast cancer remain poorly understood. Co-targeting of chromosomal instability may potentially reduce the prevalent escape mechanisms that reduce the effectiveness of cyclin-dependent kinase inhibitors. ABSTRACT: Cyclin-dependent kinases (CDKs) govern cell-cycle checkpoint transitions necessary for cancer cell proliferation. Recent developments have illustrated nuanced important differences between mono CDK inhibitor (CDKI) treatment and the combination therapies of breast cancers. The CDKIs that are currently FDA-approved for breast cancer therapy are oral agents that selectively inhibit CDK4 and CDK6, include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). CDKI therapy is effective in hormone receptor positive (HR(+)), and human epidermal growth factor receptor two negative (HER2(−)) advanced breast cancers (ABC) malignancies, but remains susceptible due to estrogen and progesterone receptor overexpression. Adding a CDK4/6I to endocrine therapy increases efficacy and delays disease progression. Given the side effects of CDKI, identifying potential new treatments to enhance CDKI effectiveness is essential. Recent long-term studies with Palbociclib, including the PALLAS and PENELOPE B, which failed to meet their primary endpoints of influencing progression-free survival, suggest a deeper mechanistic understanding of cyclin/CDK functions is required. The impact of CDKI on the anti-tumor immune response represents an area of great promise. CDKI therapy resistance that arises provides the opportunity for specific types of new therapies currently in clinical trials.