Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal.
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.
Sotillo
Rocio
R
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Schvartzman
Juan-Manuel
JM
Socci
Nicholas D
ND
Benezra
Robert
R
D000782:Aneuploidy; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D043171:Chromosomal Instability / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D064246:Mad2 Proteins; D051379:Mice; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology; D009857:Oncogenes / Q000235:genetics / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)