Review Article | Published:

Cell cycle proteins as promising targets in cancer therapy

Nature Reviews Cancer volume 17, pages 93115 (2017) | Download Citation

Abstract

Cancer is characterized by uncontrolled tumour cell proliferation resulting from aberrant activity of various cell cycle proteins. Therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrate that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. By contrast, many cancers are uniquely dependent on these proteins and hence are selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. In this Review, we focus on proteins that directly regulate cell cycle progression (such as cyclin-dependent kinases (CDKs)), as well as checkpoint kinases, Aurora kinases and Polo-like kinases (PLKs). We discuss the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as the future therapeutic potential of various cell cycle inhibitors.

Key points

  • Many cell cycle proteins are overexpressed or overactive in human cancers, in particular, D-type and E-type cyclins, cyclin-dependent kinases (CDK4, CDK6 and CDK2), Polo-like kinase 1 (PLK1) and Aurora kinases (Aurora A and Aurora B). In transgenic mice, overexpression of several of these cell cycle proteins induces or contributes to tumorigenesis, revealing their prominent oncogenic roles.

  • Some of these cell cycle proteins are also required for tumorigenesis, and their ablation in mice impairs tumour formation induced by specific genetic lesions or by carcinogen treatment, as demonstrated for several cyclins (D1, D2 and D3) and CDKs (CDK4, CDK6, CDK2 and CDK1), as well as for checkpoint kinase 1 (CHK1). Importantly, in some cases the continued presence of a cell cycle protein has also been shown to be required for tumour maintenance and progression, for example, for cyclin D1, cyclin D3 and CDK4, thereby providing a clear rationale for targeting these proteins in cancer treatment.

  • Kinases involved in cell cycle checkpoint function such as CHK1 and WEE1 also constitute potential therapeutic targets. Their inhibition compromises checkpoint function, causes excessive DNA damage and eventually leads to apoptosis, particularly in cells with compromised p53 function.

  • CDK4/6-selective inhibitors, such as palbociclib, ribociclib and abemaciclib, have shown significant benefits in clinical studies, particularly in breast cancer, but also in non-small-cell lung cancer, melanoma and head and neck squamous cell carcinoma. Importantly, following demonstration of a substantial improvement in progression-free survival, combination of palbociclib and letrozole received accelerated approval for first-line treatment of patients with advanced ER+HER2 breast cancer.

  • Inhibitors of PLK1, such as rigosertib and volasertib, have also shown encouraging results in clinical phase II/III studies for patients with myelodysplastic syndromes and acute myelogenous leukaemia, respectively, and several phase III trials are currently ongoing.

  • Compounds targeting Aurora A, particularly alisertib, have been extensively studied in preclinical models and demonstrated synergy with many other targeted therapies, leading to tumour regression in various cancer models. Moreover, clinical studies revealed encouraging activity of alisertib in peripheral T cell lymphoma, non-Hodgkin lymphoma, non-small-cell lung cancer and breast cancer.

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Acknowledgements

The authors thank S. Goel for advice and critical discussions related to the clinical data in this manuscript. This work was supported by R01 CA132740, R01 CA202634 and P01 CA080111 (to P.S.).

Author information

Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02215, USA.

    • Tobias Otto
    •  & Piotr Sicinski
  2. Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany.

    • Tobias Otto

Authors

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  2. Search for Piotr Sicinski in:

Competing interests

P.S. declares that he is a consultant for and receives research funding from Novartis.

Corresponding author

Correspondence to Piotr Sicinski.

Supplementary information

PDF files

  1. 1.

    Supplementary information S1 (table)

    Genetic mouse models that revealed the role of cell cycle proteins in tumorigenesis

  2. 2.

    Supplementary information S2 (table)

    Inhibitors of cell cycle proteins in clinical development

  3. 3.

    Supplementary information S3 (table)

    Clinical trial results of selected CDK inhibitors

  4. 4.

    Supplementary information S4 (table)

    Ongoing clinical phase III studies of selected inhibitors of cell cycle proteins

  5. 5.

    Supplementary information S5 (table)

    Clinical trial results of selected inhibitors of other cell cycle proteins

Glossary

Cell cycle checkpoints

Surveillance pathways that monitor the occurrence of DNA damage (DNA damage checkpoints), as well as proper assembly of the mitotic spindle (spindle assembly checkpoint), and can transiently arrest the cell cycle to allow time for repair or proper assembly.

Mitogenic factors

Growth-promoting factors (such as the epidermal growth factor) that induce intracellular mitogenic signalling pathways that are required for proliferation of normal cells. Cancer cells proliferate independently of mitogenic factors as a result of mutations in proteins in these signalling pathways or owing to constitutive activation of the cell cycle machinery.

Spindle assembly checkpoint

(SAC). A cell cycle checkpoint that monitors the correct attachment of the chromosomes to the mitotic spindle during metaphase. Its activation induces cell cycle arrest via inhibition of the anaphase-promoting complex/cyclosome (APC/C).

Breast cancer

Breast cancer is commonly divided into three clinical subgroups: hormone receptor-positive (ER+ or HR+) breast cancer with expression of oestrogen receptor (ER) and/or progesterone receptor (PR) and with normal ERBB2 expression; HER2+ breast cancer with ERBB2 amplification or overexpression; triple-negative breast cancer (TNBC) with low or absent expression of ER and PR and without ERBB2 overexpression.

Anaphase-promoting complex/cyclosome

(APC/C). An E3 ubiquitin ligase complex that targets mitotic cyclins and other mitotic regulators for proteasomal degradation to enable chromosome segregation during metaphase-to-anaphase transition. It contains the F-box protein cell division cycle 20 (CDC20) (APC/CCDC20), which is later replaced by CDH1 (APC/CCDH1) to maintain APC/C activity during mitotic exit and G1 phase.

Xenografts

Transplantation of human cancer cells (either cancer cell lines or patient-derived primary cancer specimens) into immunocompromised mice — either under the skin (subcutaneous) or into the location of the original tumour (orthotopic).

Chromosomal passenger complex

(CPC). A tetrameric protein complex that is essential for various mitotic events including chromosome condensation, chromosome segregation and cytokinesis. It consists of Aurora B, the inner centromeric protein (INCENP), Borealin and Survivin.

Mitotic catastrophe

A particular form of apoptosis that occurs during mitosis as a result of aberrant chromosome segregation or DNA damage, typically related to inactivation of cell cycle checkpoints.

Synthetic lethality

With regard to cancer therapy, this concept postulates that inhibition of a specific protein is lethal for cancer cells harbouring a particular mutation while sparing normal cells without that mutation. As a result, drugs provoking synthetic lethality are expected to have a higher therapeutic index.

Pan-CDK inhibitors

Inhibitors of cyclin-dependent kinases (CDKs) with a broad specificity (that is, not selective for individual CDKs).

Clinical trials

New agents with promising preclinical results (animal models) are first tested for safety (adverse effects), optimal dosage and preliminary signs of efficacy (phase I), then for their efficacy using the optimal dosage in a defined, small group of patients (phase II) and, finally, in a large, randomized, double-blind study in comparison with a placebo or the current gold standard of treatment (phase III).

Therapeutic index

The ratio between the drug dose causing the desired pharmacological effect and the dose causing toxicity (for example, toxicity or lethality in 50% of patients or animals, respectively).

Complete response

(CR). Complete disappearance of all tumours in a given patient.

Partial response

(PR). Tumour shrinkage by 30% or more in a patient.

Stable disease

(SD). Tumour shrinkage of less than 30% or tumour growth of less than 20% in a patient.

Progression-free survival

(PFS). The time from the start of cancer treatment until progression of the disease (for example, tumour growth ≥20%) or death of a patient. Although informative, an improvement in the median PFS is only a preliminary indication of therapeutic success.

Overall survival

(OS). The time from the start of cancer treatment until death of a patient. An improvement in OS (compared with the standard-of-care) is considered evidence of therapeutic success of a therapy.

Replication catastrophe

A form of DNA damage involving DNA double-strand breaks and chromosome fragmentation. Replication catastrophe occurs during S phase as a result of unscheduled firing of DNA replication origins that causes breakage of stalled replication forks. It is typically related to an impaired ataxia telangiectasia and Rad3-related (ATR)- and checkpoint kinase 1 (CHK1)-dependent DNA damage checkpoint.

Event-free survival

(EFS). The time from the start of cancer treatment until the occurrence of defined events such as certain complications or the recurrence of cancer.

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DOI

https://doi.org/10.1038/nrc.2016.138

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