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

Abstract

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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Figure 1: Mad2 overexpression cooperates with Kras G12D in lung tumorigenesis.
Figure 2: Mad2 overexpression increases aneuploidy but is not enough to overcome oncogene addiction.
Figure 3: Chromosomal instability increases the likelihood of recurrence in Kras tumours.
Figure 4: Recurrent tumours from TI-KM mice are heterogeneous and highly aneuploid.

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Gene Expression Omnibus

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The raw and processed microarray data are deposited at GEO under accession number GSE19753.

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Acknowledgements

We thank H. Varmus and W. Pao for the CCSP–rtTA and TetO–Kras mice; K. Politi, K. Podsypanina and M. Jechlinger for reagents, discussions and critical reading of the manuscript; C. Le and M. Lupu for MR imaging; M. Leversha, C. Kalyani and J. McGuire for FISH staining; K. M. D. La Perle, M. Jiao and M. Squatrito for immunohistochemistry and pathological analysis; A. Viale for CGH and Affymetrix; and Y. Chin, S. Curelariu and C. Coker for excellent technical assistance. Support was provided to R.S. by the Charles H. Revson Foundation, to J.M.S. by a Breast Cancer Research Program (BCRP) Predoctoral Traineeship Award from the US Department of Defense (Congressionally Directed Medical Research Programs) and to R.B. by the National Institutes of Health.

Author Contributions R.S., J.M.S. and R.B. designed the study. R.S. performed experiments. R.S., J.M.S., N.S. and R.B. analysed the data. R.S., J.M.S. and R.B. wrote the paper.

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Correspondence to Robert Benezra.

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Sotillo, R., Schvartzman, JM., Socci, N. et al. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature 464, 436–440 (2010). https://doi.org/10.1038/nature08803

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