Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Nature. 2010 Mar 18;464(7287):436-40. doi: 10.1038/nature08803. Epub 2010 Feb 21.
Inhibition of an initiating oncogene often leads to extensive tumour cell death, a phenomenon known as oncogene addiction. This has led to the search for compounds that specifically target and inhibit oncogenes as anticancer agents. However, there has been no systematic exploration of whether chromosomal instability generated as a result of deregulation of the mitotic checkpoint pathway, a frequent characteristic of solid tumours, has any effect on oncogene addiction. Here we show that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 in mice does not affect the regression of Kras-driven lung tumours when Kras is inhibited. However, tumours that experience transient Mad2 overexpression and consequent chromosome instability recur at markedly elevated rates. The recurrent tumours are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early chromosomal instability may be responsible for tumour relapse after seemingly effective anticancer treatments.
抑制起始致癌基因通常会导致大量肿瘤细胞死亡，这种现象称为致癌基因成瘾。这导致了寻找专门针对致癌基因并抑制其作为抗癌药物的化合物的研究。然而，人们尚未系统地探讨由于有丝分裂检查点途径失调而产生的染色体不稳定性（实体瘤的常见特征）是否对致癌基因成瘾有任何影响。在这里，我们表明，在用有丝分裂检查点基因 Mad2 过表达诱导染色体不稳定性时，当抑制 Kras 时，不会影响 Kras 驱动的肺肿瘤的消退。但是，经历短暂 Mad2 过表达和随后的染色体不稳定性的肿瘤以明显升高的速率复发。复发性肿瘤高度非整倍体，并伴有不同程度的促增殖途径的激活。因此，早期染色体不稳定性可能是抗癌治疗后肿瘤复发的原因。
