Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer
Abstract
:1. Introduction
2. CDK4/6 Are Good Targets in ER+ Breast Cancer
3. The Three Approved CDK4/6 Inhibitors
3.1. Palbociclib
3.2. Ribociclib
3.3. Abemaciclib
4. Emergence of Intrinsic and Acquired Resistance to CDK4/6 Inhibitors
4.1. Intrinsic
4.2. Acquired
5. Mechanisms of Resistance to CDK4/6 Inhibitors
5.1. Cyclin D1–CDK4/6–Rb Activation
5.2. Cyclin E1/CDK2 Activation
5.3. PI3K–AKT Activation
5.4. KRAS Activation
5.5. Autophagy and Lysosomal Activity
5.6. FAT1 Loss
5.7. FGFR1 Activation
5.8. MDM2 Dysregulation
5.9. mTOR Activation
5.10. Increased G2M Activity: WEE1 and CDK7 Overexpression
6. Possible Therapies to Target Intrinsic or Acquired Resistance to CDK4/6 Inhibitors
6.1. Antiestrogens
6.2. PI3K Inhibitors
6.3. mTOR Inhibitors
6.4. FGFR Inhibitors
6.5. CDK2 Inhibitors
6.6. Chemotherapy
6.7. Autophagy Inhibitors
6.8. eIF4A Inhibitors
6.9. MDM2 Inhibitors
6.10. Immunotherapy
6.11. G2/M Checkpoint Inhibition
7. Preventing Resistance to CDK4/6 Inhibitors
8. Conclusions and Future Directions
9. Materials and Methods
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Scheidemann, E.R.; Shajahan-Haq, A.N. Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer. Int. J. Mol. Sci. 2021, 22, 12292. https://doi.org/10.3390/ijms222212292
Scheidemann ER, Shajahan-Haq AN. Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer. International Journal of Molecular Sciences. 2021; 22(22):12292. https://doi.org/10.3390/ijms222212292
Chicago/Turabian StyleScheidemann, Erin R., and Ayesha N. Shajahan-Haq. 2021. "Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer" International Journal of Molecular Sciences 22, no. 22: 12292. https://doi.org/10.3390/ijms222212292