Mad2-induced chromosome instability leads to lung tumor relapse after oncogene withdrawal

Inhibition of an initiating oncogene often leads to extensive tumor cell death, a phenomenon known as oncogene addiction1. This has led to the search for compounds that specifically target and inhibit oncogenes as anti-cancer agents. Whether chromosomal instability (CIN) generated as a result of deregulation of the mitotic checkpoint pathway2,3, a frequent characteristic of solid tumors, has any effect on oncogene addiction, however, has not been explored systematically. We show here that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 does not affect the regression of Kras driven lung tumors upon Kras inhibition. However, tumors that experience transient Mad2 overexpression and consequent chromosome instability recur at dramatically elevated rates. The recurrent tumors are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early CIN may be responsible for tumor relapse after seemingly effective anti-cancer treatments.