Genomic instability has been implicated in tumorigenesis. In a new mouse model for Kras-driven lung tumours in which genomic instability is caused by overexpression of the spindle checkpoint protein Mad2, Sotillo et al. find that switching off the Kras oncogene still leads to cancer regression, but tumours recur at a much higher rate. This suggests that genomic instability not only promotes tumorigenesis but may also contribute to recurrences after cancer therapy and possibly to therapeutic resistance. Genomic instability has been implicated in tumour development. Here, a new mouse model of Kras-driven lung tumours has been developed, in which genomic instability is caused by overexpression of the mitotic checkpoint protein Mad2. In this model, inhibiting Kras leads to tumour regression, as shown previously. But tumours recur at a much higher rate. Inhibition of an initiating oncogene often leads to extensive tumour cell death, a phenomenon known as oncogene addiction1. 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 pathway2,3, 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.

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