Intrinsic and acquired resistance to CDK4/6 inhibitors and potential overcoming strategies.

Abstract

Abnormal activation of the cyclin-dependent kinases (CDKs), which result in aberrant cell proliferation, is one of the inherent characteristics of tumor. Thus targeting the activity of CDKs represents a promising tumor therapeutic strategy. Currently, the specific inhibitors that target CDK4 and CDK6 have been approved for the treatment of estrogen receptor positive, human epidermal growth factor receptor 2 negative (ER+ HER2-) breast cancer in combination with endocrine therapy; other combination strategies are being tested in a number of clinical trials. However, the acquired resistance to CDK4/6 inhibitors has emerged. As the cell cycle is orchestrated by a series of biological events, the alterations of other molecular events that regulate the cell cycle progression may be involved in intrinsic resistance to CDK4/6 inhibitors. In this review we mainly discuss the mechanisms underlying intrinsic resistance and acquired resistance to CDK4/6 inhibitors as well as combination strategies with other signal pathway inhibitors being tested in clinical and pre-clinical studies, to extend the use of CDK4/6 inhibitors in tumor treatment.

• Authors: Xia-Qing Xu, Xiao-Hui Pan, Ting-Ting Wang, Jian Wang, Bo Yang, Qiao-Jun He, Ling Ding
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 42 Issue 2 Pg. 171-178 (Feb 2021) ISSN: 1745-7254 [Electronic] United States
• PMID: 32504067 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• Drug Resistance, Neoplasm
• Female
• Humans
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)