CDK4/6 inhibitor resistance mechanisms and treatment strategies (Review)

Abstract

In recent years, the incidence rate of breast cancer has increased year by year, and it has become a major threat to the health of women globally. Among all breast cancer subtypes, the hormone receptor (HR)⁺/human epidermal growth factor receptor 2 (HER2)^‑ luminal subtype breast cancer is the most common form of breast cancer. Cyclin‑dependent kinase 4 and 6 (CDK4/6) inhibitors, the hotspots in the field of targeted therapy for breast cancer, have proved to exhibit a good effect on patients with HR⁺/HER2^‑ breast cancer in a number of clinical trials, but the problem of drug resistance is inevitable. At present, three specific CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have been approved by the USA Food and Drug Administration for the first‑line treatment of HR⁺/HER2^‑ breast cancer. The drug resistance mechanisms of CDK4/6 inhibitors can be divided into cell cycle‑specific resistance and cell cycle non‑specific resistance. With the discovery of the drug resistance mechanism of CDK4/6 inhibitors, various targeted strategies have been proposed. The present review mainly discusses the mechanism of CDK4/6 inhibitors, drug resistance mechanisms and treatment strategies after resistance.

Keywords: CDK4/6; breast cancer; drug resistance; mechanisms; strategies.

Figure 1

Top 10 cancer types with regard to estimated new cases and cancer-associated deaths in the United States in 2022.

Figure 2

Mechanism of CDK4/6 inhibitors. CDK, cyclin-dependent kinase; RB, retinoblastoma protein.

Figure 3

Cell cycle-specific mechanisms for the resistance to CDK4/6 inhibitors. CDK, cyclin-dependent kinase; RB, retinoblastoma protein; CHK1, checkpoint kinase 1; HDAC, histone deacetylases; HDACi, histone deacetylases inhibitor; INK4, inhibitor of CDK4; WEE1, WEE1 G2 checkpoint kinase; FZR1, fizzy and cell division cycle 20-related 1; VEGF-A, vascular endothelial growth factor A; MDM2, mouse double minute 2 homolog; ER, estrogen receptor; CIP/KIP, CDK interaction protein/kinase inhibitor protein; P, phosphate; CDK4/6i, CDK4/6 inhibitor; miR/miRNA, microRNA; APC/C, anaphase-promoting complex.

Figure 4

Cell cycle non-specific mechanisms for the resistance to CDK4/6 inhibitors. FGF2, fibroblast growth factor 2; FGFR1, fibroblast growth factor receptor 1; ER, estrogen receptor; AR, androgen receptor; PDK1, 3-phosphoinositide-dependent protein kinase-1; DHT, 5-α-dihydrotestosterone; AP-1, activator protein 1; EMT, epithelial-mesenchymal transition; RB, retinoblastoma protein; P, phosphate; FAT1, FAT atypical cadherin 1; YAP, yes-associated protein; PIP, prolactin-induced protein; Smad, drosophila mothers against decapentaplegic protein.

Figure 5

Treatment strategies after CDK4/6 inhibitor resistance. CDK, cyclin-dependent kinase.