Journal Article

Cell cycle proteins as promising targets in cancer therapy

Sicinski, Piotr, Otto, Tobias

2017

Overview

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. Proteins regulating cell cycle progression are involved in the formation of most cancer types. This Review discusses the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment, results of clinical trials, as well as future therapeutic potential of various cell cycle inhibitors. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/45/612/1223 / 631/67/1059/602 / 631/67/1244 / 631/67/395 / 631/80/641/2187 / Animals / Aurora Kinase A - antagonists & inhibitors / Aurora Kinase A - physiology / Biomedicine / Cancer / Cancer Research / Cancer treatment / Care and treatment / Cell cycle / Cell Cycle Proteins - antagonists & inhibitors / Cell Cycle Proteins - physiology / Checkpoint Kinase 1 - antagonists & inhibitors / Checkpoint Kinase 1 - physiology / Clinical Trials as Topic / Cyclin-Dependent Kinase 2 - antagonists & inhibitors / Cyclin-Dependent Kinase 2 - physiology / Cyclin-Dependent Kinase 4 - antagonists & inhibitors / Cyclin-Dependent Kinase 4 - physiology / Cyclin-Dependent Kinase 6 - antagonists & inhibitors / Cyclin-Dependent Kinase 6 - physiology / Humans / MicroRNA / Neoplasms - drug therapy / Nuclear Proteins - antagonists & inhibitors / Nuclear Proteins - physiology / Polo-Like Kinase 1 / Protein Serine-Threonine Kinases - antagonists & inhibitors / Protein Serine-Threonine Kinases - physiology / Protein-Tyrosine Kinases - antagonists & inhibitors / Protein-Tyrosine Kinases - physiology / Proteins / Proto-Oncogene Proteins - antagonists & inhibitors / Proto-Oncogene Proteins - physiology / review-article / Signal Transduction