Resistance to CDK4/6 inhibition: Mechanisms and strategies to overcome a therapeutic problem in the treatment of hormone receptor-positive metastatic breast cancer
Source : https://www.sciencedirect.com/science/article/abs/pii/S0167488922001380?via=ihub
Palbociclib, ribociclib and abemaciclib are selective CDK4/6 inhibitors, approved for HR+, HER2-, advanced or metastatic breast cancer * Various mechanisms of primary ( de novo) or acquired resistance to CDK4/6 inhibitors have been described * There are possible treatment strategies that could help overcome resistance to CDK4/6 inhibitors Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have been approved in combination with hormone therapy for the treatment of patients with HR+, HER2-negative advanced or metastatic breast cancer (mBC).
Relevance: This review presents the currently available knowledge on the mechanisms of resistance to CDK4/6 inhibitors, explores possible treatment strategies that could overcome this therapeutic problem, and summarizes relevant recent clinical trials.
• Source: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
• Conclusion/Relevance: “This review presents the currently available knowledge on the mechanisms of resistance to CDK4/6 inhibitors, explores possible treatment strategies that could overcome this therapeutic problem, and summarizes relevant recent clinical trials.”
• CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have been approved in combination with hormone therapy for HR+, HER2-negative advanced/metastatic breast cancer.
• About 10% of patients exhibit de novo resistance, and the remainder exhibit acquired resistance after 24 to 48 months on first-line therapy. When CDK4/6 inhibitors are used as second-line therapy, acquired resistance manifests even more quickly.
• Resistance mechanisms include cell cycle-related mechanisms include p16 amplification, CDK6/CDK4 amplification, and cyclin E-CDK2 amplification. Other methods of bypass include the activation of FGFR or PI3K/AKT/mTOR pathways.
• The authors wrote, “Identifying the different mechanisms by which resistance to CDK4/6 inhibitors occurs may help to design new treatment strategies to improve patient outcomes.”