Targeting Cell Cycle Vulnerabilities in Cancers: Emerging Strategies for Therapeutic Development

Cell division is a fundamental cellular process that ensures propagation of genetic material to daughter cells. This process relies on the fidelity of DNA replication and chromosome segregation and is primarily regulated by sequential activity of cyclin-dependent kinases (Cdks) in the cell cycle program. Mitogenic signals lead to the activation of Cdks and promote cell cycle progression, whereas checkpoints act as surveillance systems to halt cell cycle progression in response to abnormal conditions. In cancers, these regulatory networks are frequently disrupted due to continuous activation of mitogenic/oncogenic signaling and/or loss of checkpoint control, resulting in uncontrolled cell cycle progression and thus genome instability. Nevertheless, cancer cells often maintain robust cell cycle control by virtue of compensatory mechanisms. Counterintuitively, however, this apparent robustness increases sensitivity to perturbations and creates unique targetable vulnerabilities. Intervening in these vulnerabilities in the cell cycle control is therefore the rationale for the effective and selective cancer treatment. In this review, we summarize emerging insights into how we can interfere with cancer cell proliferation by targeting the cancer specific vulnerabilities arising from cell cycle dysregulation. We highlight advances in targeting Cdks, checkpoint kinases and mitotic kinases, as well as recent discoveries from CRISPR-genetic screens that reveal synthetic lethal genes. Understanding these vulnerabilities provides a framework for developing cancer therapies that exploit specific dependencies in cell cycle control.