Targeting cell-cycle machinery in cancer

Abstract

Abnormal activity of the core cell-cycle machinery is seen in essentially all tumor types and represents a driving force of tumorigenesis. Recent studies revealed that cell-cycle proteins regulate a wide range of cellular functions, in addition to promoting cell division. With the clinical success of CDK4/6 inhibitors, it is becoming increasingly clear that targeting individual cell-cycle components may represent an effective anti-cancer strategy. Here, we discuss the potential of inhibiting different cell-cycle proteins for cancer therapy.

Figure 1.. Overview of the cell-cycle.

Please see Box 1 for details. Activation of cyclin D-CDK4/6 kinases triggers a cascade of events resulting in activation of E2F-dependent transcriptional program. DP1, the dimerization partner of E2F transcription factors. Examples of E2F targets are provided in a grey rectangle. Multiple proteins (such as ORC, CDC6, MCMs) assemble on DNA replication origins during the G1 phase, resulting in DNA origin licensing. Subsequent phosphorylations (P) by DBF4-CDC7 and cyclin E-CDK2 activate the DNA helicase and trigger origin firing and entry of cells into the S-phase. During S-phase, cyclin A-CDK2 phosphorylates components of the DNA replication machinery. In G2-phase, cyclin A activates cyclin B-CDK1. Cyclin B is localized in the cytoplasm during G2-phase, but it translocates into the nucleus upon being phosphorylated by PLK1. Inhibitory phosphorylations of CDK1 provided by WEE1 and MYT1 kinases are removed by the CDC25 phosphatase family. Activation of cyclin-CDK complexes is also carried out by cyclin H-CDK7-MAT1 (CAK1) complex. Upon activation, cyclin B-CDK1 phosphorylates components of the mitotic machinery. Blue and pink ovals denote, respectively, positive and negative regulators of the cell-cycle.

Figure 2.. Regulation of cell-cycle machinery by proteasomal degradation.

E3 ubiquitin ligases ascertain unperturbed cell cycle progression by governing timely degradation of various cell-cycle proteins. Light green rounded rectangles and ovals represent ubiquitin ligase complexes and their respective activators/f-box proteins. Ub in a purple circle indicates ubiquitination. FBXW7 - F-Box and WD Repeat Domain Containing 7; Cul-3 – Cullin 3; SKP2 – S-Phase Kinase Associated Protein 2; βTrCP - Beta-Transducin Repeat Containing E3 Ubiquitin Protein Ligase.

Figure 3.. The landscape of genetic alterations within the core cell-cycle machinery genes.

Data according to The Cancer Genome Atlas PanCancer (n=10,967 samples). Shown is the frequency of alterations within groups of the indicated cell-cycle genes. Ten most affected cancer types are shown for each group, together with percentages of cases displaying genetic alterations. Tumor type designation: ACC - Adrenocortical Carcinoma; BLCA - Bladder Urothelial Carcinoma; BRCA - Breast Invasive Carcinoma; CESC - Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma; CHOL – Cholangiocarcinoma; COADREAD - Colorectal Adenocarcinoma; DLBC - Diffuse Large B-cell Lymphoma; ESCA - Esophageal Carcinoma, GBM - Glioblastoma Multiforme, HNSC - Head and Neck Squamous Cell Carcinoma, LIHC - Liver Hepatocellular Carcinoma, LUAD – Lung Adenocarcinoma, LUSC- Lung Squamous Cell Carcinoma, MESO – Mesothelioma, OV - Ovarian Serous Cystadenocarcinoma, PAAD - Pancreatic Adenocarcinoma, PRAD - Prostate Adenocarcinoma, SARC – Sarcoma, SKCM - Skin Cutaneous Melanoma, STAD - Stomach Adenocarcinoma, UCEC - Uterine Corpus Endometrial Carcinoma, UCS - Uterine Carcinosarcoma, UVM - Uveal Melanoma.

Figure 4.

Inhibitors of cell-cycle proteins and their major non-cell-cycle CDK targets.