Review Article

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

Authors: Xia-qing Xu1, Xiao-hui Pan1, Ting-ting Wang1, Jian Wang1, Bo Yang1, Qiao-jun He1, Ling Ding1
1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Correspondence to: Qiao-jun He: qiaojunhe@zju.edu.cn, Ling Ding: ld362@zju.edu.cn,
DOI: 10.1038/s41401-020-0416-4
Received: 28 September 2019
Accepted: 1 April 2020
Advance online: 5 June 2020

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.
Keywords: cancer; cell cycle; Rb; CDK4/6 inhibitors; intrinsic resistance; acquired resistance

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