Cell cycle on the crossroad of tumorigenesis and cancer therapy

• Published in: Trends in cell biology Vol. 32; no. 1; pp. 30 - 44
• Main Authors: Liu, Jing, Peng, Yunhua, Wei, Wenyi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2022; Elsevier BV
• Subjects: Cancer; cancer immune; Cancer therapies; Carcinogenesis; Cell Cycle; Cell Transformation, Neoplastic; Chimeras; Cycle ratio; degradation; Humans; Immunosurveillance; Metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; PROTAC; Proteolysis; Therapeutic targets; Tumorigenesis; cancer; metabolism; degradation; cell cycle; PROTAC; cancer immune
• ISSN: 0962-8924; 1879-3088; 1879-3088
• DOI: 10.1016/j.tcb.2021.07.001

Aberrancy in cell cycle progression is one of the fundamental mechanisms underlying tumorigenesis, making regulators of the cell cycle machinery rational anticancer therapeutic targets. A growing body of evidence indicates that the cell cycle regulatory pathway integrates into other hallmarks of cancer, including metabolism remodeling and immune escape. Thus, therapies against cell cycle machinery components can not only repress the division of cancer cells, but also reverse cancer metabolism and restore cancer immune surveillance. Besides the ongoing effects on the development of small molecule inhibitors (SMIs) of the cell cycle machinery, proteolysis targeting chimeras (PROTACs) have recently been used to target these oncogenic proteins related to cell cycle progression. Here, we discuss the rationale of cell cycle targeting therapies, particularly PROTACs, to more efficiently retard tumorigenesis. The cell cycle machinery regulates cancer metabolism primarily at the post-translational level, either through phosphorylation of metabolic enzymes or upstream regulators by CDKs or through ubiquitination of these proteins by APC/C or SCF E3 ligases.CDK inhibitors restore cancer immune surveillance, in part by triggering tumor antigen presentation or stimulating the infiltration of immune cells into the tumor, thus providing synergetic effects with immune checkpoint blockade (ICB).Proteolysis targeting chimeras (PROTACs) provide a new cancer therapeutic approach to target cell cycle machinery components with oncogenic roles for proteasomal degradation, which has advantages over traditional small molecular inhibitors (SIMs) in many aspects including distinguishing the protein target from close family members, overcoming potential drug resistance, and repressing the kinase-independent function of protein targets.