review · The FASEB Journal
Uncontrolled cell division caused by the disruption of cell cycle regulators is a defining feature of cancer. Key molecular components, including cyclins, cyclin-dependent kinases, checkpoint kinases, and mitotic regulators, drive tumour development when altered or overexpressed. Therapeutic intervention targeting these mechanisms has shown potential, notably through the application of CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib in treating breast cancer. Other identified molecular targets include the anaphase-promoting complex/cyclosome, Skp2, p21, and aurora kinases. However, treatment resistance continues to restrict broader clinical effectiveness. Overcoming these barriers requires the development of next-generation inhibitor compounds, targeted combination treatment strategies, and reliable predictive biomarkers to guide appropriate patient selection across different types of cancer.
Cancer cells multiply uncontrollably by hijacking normal cell division processes. Pinpointing the exact proteins that regulate this cycle allows researchers and clinicians to design precise drug therapies. Understanding both the current successes and the ongoing issue of drug resistance helps guide the creation of more effective, tailored cancer treatments that can improve patient survival.
This research informs oncology drug discovery for pharmaceutical developers and clinical researchers. Established CDK4/6 inhibitors represent approved treatments, whereas other interventions, such as aurora kinase or APC/C inhibitors, remain earlier in the pipeline. Advancing these approaches towards broader commercial and clinical use requires developing next-generation compounds, testing combination regimens, and validating diagnostic biomarkers to identify patients most likely to respond.
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The cell cycle is tightly regulated to ensure controlled cell proliferation. Dysregulation of the cell cycle machinery is a hallmark of cancer that leads to unchecked growth. This review comprehensively analyzes key molecular regulators of the cell cycle and how they contribute to carcinogenesis when mutated or overexpressed. It focuses on cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, checkpoint kinases, and mitotic regulators as therapeutic targets. Promising strategies include CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib for breast cancer treatment. Other possible targets include the anaphase-promoting complex/cyclosome (APC/C), Skp2, p21, and aurora kinase inhibitors. However, challenges with resistance have limited clinical successes so far. Future efforts should focus on combinatorial therapies, next-generation inhibitors, and biomarkers for patient selection. Targeting the cell cycle holds promise but further optimization is necessary to fully exploit it as an anti-cancer strategy across diverse malignancies.
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DOI: 10.1096/fj.202400769r
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