Targeting the cell cycle in breast cancer: towards the next phase

Abstract

Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.

Keywords: CDK4/6 inhibitor; PLK4; TTK; breast cancer; drug resistance.

Figure 1.

The mammalian cell cycle is governed by CDKs, cyclins, and ubiquitin ligases. Genomic integrity is guarded by multiple checkpoints and inhibitors (red) that halt cell cycle progression in the absence of appropriate environmental stimuli, in the presence of DNA damage, or when chromosomes are not sufficiently aligned in mitosis. The centrosome cycle, depicted in green, is important for generating the bipolar spindle apparatus to enable proper chromosome segregation.

Figure 2.

Targeting the cell cycle in breast cancer. (a) Cell cycle vulnerabilities of HR+ breast tumours. The Rb/E2F/CDK4/6 pathway is generally competent in HR+ breast cancers, making these cells dependent on CDK4/6 for progression through the restriction point. In such cells with intact Rb, CDK4/6 inhibitors induce cell cycle arrest in G0/G1. (b) Potential mechanisms of resistance to CDK4/6 inhibitors in HR+ breast cancers. To overcome resistance to CDK4/6 inhibition, cells acquire molecular alterations that enable them to bypass the restriction point and uncouple their dependency on CDK4/6 activity for cell cycle progression. (c) Cell cycle vulnerabilities of TNBC tumours. TNBC tumours are typically TP53 mutant, highly aneuploid, and often exhibit centrosome amplification. These features make TNBC cells susceptible to the induction of further, intolerable, aneuploidy and multipolar spindle formation. TTK and PLK4 inhibitors potentiate genomic instability and chromosome segregation errors in mitosis leading to cell death. (d) Potential mechanisms of resistance to TTK inhibition in TNBC. Gatekeeper mutations in TTK and delay of mitotic exit through impaired function of the APC/C have been demonstrated to confer resistance to TTK targeting drugs. Blue arrows/type indicate DNA amplification or activating mutations. Dashed lines indicate loss of activity/function. * indicates a gatekeeper mutation. Cell cycle checkpoints are indicated in red.

Figure 3.

Strategies for identifying clinical correlates of drug response and combination or sequential therapies to overcome drug resistance. (a) Approaches to elucidate resistance mechanisms, vulnerabilities of drug resistant cells, and biomarkers predictive of drug response. (b) Re-purposing TTK inhibitors for the treatment of CDK4/6 inhibitor-resistant breast cancer. PGx = pharmacogenomics. PDX = patient-derived xenograft. ct-DNA = circulating tumour DNA. ET = endocrine therapy. SAC = spindle assembly checkpoint.