The Role of Cyclin-Dependent Kinases in the Cell Cycle
To understand what drugs are CDK inhibitors, one must first grasp the role of cyclin-dependent kinases ($CDKs$) in cell biology. $CDKs$ are a family of enzymes that, with proteins called cyclins, regulate the cell cycle, controlling progression through phases like G1, S, G2, and M. In cancer, this regulation often fails, leading to overactive $CDKs$ and uncontrolled growth. CDK inhibitors, particularly those targeting $CDK4$ and $CDK6$, can halt this process, stopping cancer cell growth.
FDA-Approved CDK Inhibitors: Focus on CDK4/6
The most successful class targets $CDK4$ and $CDK6$, significantly changing treatment for hormone receptor-positive ($HR+$), human epidermal growth factor receptor 2-negative ($HER2-$) breast cancer. The main FDA-approved drugs are:
- Palbociclib (Ibrance): Approved in 2015, used with endocrine therapy for advanced breast cancer. It prevents the phosphorylation of the retinoblastoma protein, stopping cell cycle progression. Common side effects include reversible neutropenia.
- Ribociclib (Kisqali): Approved in 2017, used with endocrine therapy for advanced and high-risk early $HR+$, $HER2-$ breast cancer. It has shown improved overall survival. Side effects include neutropenia and a risk of QT prolongation requiring cardiac monitoring.
- Abemaciclib (Verzenio): Approved in 2017 for advanced and high-risk early breast cancer. It is more selective for $CDK4$ than $CDK6$, leading to less neutropenia but more diarrhea. It can be used alone in some cases.
The Mechanism of CDK Inhibition
Most CDK inhibitors block the cell cycle at the G1 checkpoint. In $HR+$ breast cancer, estrogen signaling can increase cyclin D and $CDK4/6$ activity, leading to phosphorylation of the retinoblastoma protein ($Rb$). Phosphorylated $Rb$ releases E2F, activating genes for S phase entry. Blocking $CDK4/6$ prevents $Rb$ phosphorylation, stopping cell proliferation. A comparison of approved CDK4/6 inhibitors can be found on {Link: PMC https://pmc.ncbi.nlm.nih.gov/articles/PMC10571689/}.
Other Approved and Investigational CDK Inhibitors
Beyond $CDK4/6$ inhibitors, other types exist. Trilaciclib (Cosela) is an FDA-approved CDK4/6 inhibitor used to protect bone marrow from chemotherapy in extensive-stage small cell lung cancer (ES-SCLC). Investigational CDK inhibitors are also being researched, including CDK2 inhibitors for cancers with cyclin E overexpression and pan-CDK inhibitors.
Managing Treatment and Side Effects
Managing side effects is crucial and often involves dose adjustments and supportive care. Hematologic toxicities, like neutropenia, are common with palbociclib and ribociclib. Gastrointestinal issues, particularly diarrhea, are common with abemaciclib. Cardiac monitoring is required for patients on ribociclib due to the risk of QT prolongation. Patients should report respiratory symptoms due to a risk of interstitial lung disease (ILD) and pneumonitis.
Conclusion
CDK inhibitors are effective targeted therapies that have significantly improved outcomes, particularly for $HR+$, $HER2-$ breast cancer. By specifically targeting the cell cycle, they reduce cancer cell growth while often being less toxic to healthy cells than traditional chemotherapy. The success of palbociclib, ribociclib, and abemaciclib is driving research into new inhibitors, combinations, and ways to overcome resistance. Future developments are expected to broaden the use of CDK inhibitors, further improving cancer treatment. For more information, consult reputable sources like the National Institutes of Health.
