Mitotic Machinery Dysregulation in Lung Cancer: Biological Roles, Therapeutic Targeting, and Combination Strategies

Lung cancer remains the leading cause of cancer-related mortality worldwide and is characterized by high aggressiveness and therapeutic resistance, partly driven by mitotic dysregulation. Key mitotic regulators, including kinases such as PLK1, AURKA, AURKB, and MPS1 and kinesins such as CENPE and Eg5, are frequently overexpressed in NSCLC and SCLC, contributing to chromosomal instability, aneuploidy, and highly proliferative tumor phenotypes. Although multiple inhibitors targeting these proteins have been developed, their clinical efficacy as monotherapies has been limited. This is largely due to insufficient target dependency, adaptive resistance mechanisms, mitotic slippage, activation of compensatory pathways, and dose-limiting toxicity. This review integrates current knowledge on the physiological roles of major mitotic regulators, their dysregulation in lung tumorigenesis, and the biological and pharmacological barriers that underlie the limited success of antimitotic drugs. We further highlight preclinical and clinical evidence supporting rational combination strategies designed to enhance the antitumor activity of mitotic inhibitors while minimizing toxicity. Together, these insights underscore the need for refined therapeutic approaches that better exploit vulnerabilities in mitotic control to improve outcomes for patients with lung cancer.