The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance.
Mary AbdelmalakRajanbir SinghMohammed AnwerPavel IvanchenkoAmritdeep RandhawaMyra AhmedAnthony W AshtonYanming DuXuanmao JiaoRichard G PestellPublished in: Cancers (2022)
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.
Keyphrases
- cell cycle
- cell proliferation
- cancer therapy
- clinical trial
- epidermal growth factor receptor
- immune response
- drug delivery
- free survival
- randomized controlled trial
- stem cells
- papillary thyroid
- oxidative stress
- squamous cell carcinoma
- advanced non small cell lung cancer
- cell therapy
- dna damage
- machine learning
- young adults
- combination therapy
- deep learning
- cell death
- lymph node metastasis
- childhood cancer
- metastatic breast cancer