Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

Abstract

Deregulation of the cyclin D-CDK4/6-INK4-RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle-specific mechanisms and cell cycle-nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.

Keywords: CDK4/6; drug resistance; estrogen receptor-positive breast cancer.

Figure 1

Cell cycle‐specific mechanisms for the resistance to CDK4/6 inhibitors. Multiple factors involved in the regulation of cell cycle are associated with resistance to CDK4/6 inhibitors. Loss of drug target genes, such as RB and FZR1, as well as overexpression of various genes which are directly or indirectly involved in the progression of cell cycle, as shown in Figure 1, are responsible for resistance to CDK4/6 inhibitors. Abbreviations: CDK, Cyclin dependent kinase; RB, Retinoblastoma protein; CHK1, Checkpoint kinase 1; STAT3, Signal transducer and activator of transcription 3; VEGF‐A, Vascular endothelial growth factor A; HDAC, Histone deacetylases; MDM2, Mouse double minute 2 homolog. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Cell cycle‐non specific mechanisms for the resistance to CDK4/6 inhibitors. (a) Overexpression of various factors which are upstream of the cell cycle, such as FGFR, PI3K/AKT/mTOR, and AP‐1, act as bypass pathways for the progression of the cell cycle, resulting in decreased efficacy of CDK4/6 inhibitors. Loss of ER dependence also drives cells to escape CDK4/6 inhibition. (b) TGF‐β induces the expression of several transcription factors involved in EMT via Smad and the PI3K/AKT/mTOR pathway. The cyclin‐CDK complex phosphorylates and suppresses Smad 3, recovering cell cycle arrest. In addition, inhibition of cyclin D activates autophagy, leading to the reversal of cell cycle arrest mediated by CDK4/6 inhibitors. CDK4/6 inhibitors may activate various immune‐related genes, which may also play a role in the development of resistance. Abbreviations: FGF2, fibroblast growth factor 2; FGFR1, fibroblast growth factor receptor 1; ER, estrogen receptor; TGF‐β, transforming growth factor β; MEK, Mitogen‐activated protein kinase; ERK, extracellular signal‐regulated kinases; PI3K, phosphatidylinositide 3‐kinases; mTOR, mammalian target of rapamycin; PDK1, 3‐phosphoinositide‐dependent protein kinase‐1; AP‐1, Activator protein 1; EMT, epithelial‐mesenchymal transition; NFAT, Nuclear factor of activated T‐cells; IL‐2, Interleukin‐2; DNMT, DNA methyltransferase. [Color figure can be viewed at wileyonlinelibrary.com]