New therapeutic approaches that antagonize tumour-promoting phenotypes in lung cancer are needed to improve patient outcomes. Chromosomal instability (CIN) is a hallmark of lung cancer characterized by the ongoing acquisition of genetic alterations that include the gain and loss of whole chromosomes or segments of chromosomes as well as chromosomal rearrangements during cell division. Although it provides genetic diversity that fuels tumour evolution and enables the acquisition of aggressive phenotypes like immune evasion, metastasis, and drug resistance, too much CIN can be lethal because it creates genetic imbalances that disrupt essential genes and induce severe proteotoxic and metabolic stress. As such, sustaining advantageous levels of CIN that are compatible with survival is a fine balance in cancer cells, and potentiating CIN to levels that exceed a tolerable threshold is a promising treatment strategy for inherently unstable tumours like lung cancer. Kinesins are a superfamily of motor proteins with many members having functions in mitosis that are critical for the correct segregation of chromosomes and, consequently, maintaining genomic integrity. Accordingly, inhibition of such kinesins has been shown to exacerbate CIN. Therefore, inhibiting mitotic kinesins represents a promising strategy for amplifying CIN to lethal levels in vulnerable cancer cells. In this review, we describe the concept of CIN as a therapeutic vulnerability and comprehensively summarize studies reporting the clinical and functional relevance of kinesins in lung cancer, with the goal of outlining how kinesin inhibition, or “targeting kinesins”, holds great potential as an effective strategy for treating lung cancer.
为改善肺癌患者预后，亟需开发能够拮抗肿瘤促进表型的新型治疗方法。染色体不稳定性是肺癌的重要特征，表现为细胞分裂过程中持续获得包括整条染色体或染色体片段的增益与缺失以及染色体重排在内的遗传学改变。尽管染色体不稳定性通过提供遗传多样性驱动肿瘤进化，使其获得免疫逃逸、转移和耐药等侵袭性表型，但过度的染色体不稳定性可能因造成遗传失衡、破坏必需基因功能并诱发严重的蛋白质毒性和代谢应激而导致细胞死亡。因此，癌细胞需精细维持有利于生存的染色体不稳定性水平，而将染色体不稳定性提升至可耐受阈值以上，对于肺癌这类本质不稳定的肿瘤而言是具有前景的治疗策略。驱动蛋白作为马达蛋白超家族，其众多成员在有丝分裂中发挥关键作用，对染色体正确分离及维持基因组完整性至关重要。研究表明抑制此类驱动蛋白可加剧染色体不稳定性。因此，抑制有丝分裂驱动蛋白成为在易感癌细胞中将染色体不稳定性提升至致死水平的潜在策略。本综述阐述染色体不稳定性作为治疗脆弱性的理论概念，系统总结驱动蛋白在肺癌中临床与功能相关性的研究进展，旨在阐明抑制驱动蛋白（或称"靶向驱动蛋白"）作为肺癌治疗策略的巨大潜力。
Targeting Kinesins for Therapeutic Exploitation of Chromosomal Instability in Lung Cancer
肿瘤(癌症)患者之家