Stage-specific sensitivity to p53 restoration during lung cancer progression

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Abstract

Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway1,2,3. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.

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Figure 1: Lung adenomas are apathetic to Trp53 restoration, whereas adenocarcinomas are responsive.
Figure 2: Adenocarcinoma cells are sensitive to Trp53 restoration and are specifically eliminated from lung tumours.
Figure 3: Adenocarcinomas are typified by amplified MAPK signalling.
Figure 4: Arf is specifically expressed in adenocarcinomas and sensitizes lung cancer cells to Trp53 restoration.

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Acknowledgements

We would like to thank M. DuPage and C. Kim for critical reading of the manuscript. We are indebted to D. Crowley, E. Vasile and M. Griffin at the Koch Institute Core facilities (supported by Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute). We are grateful to M. Luo for microarray support. We thank M. Leversha at MSKCC for FISH. D.M.F. has been supported by the American Cancer Society (New England Area Fellow), and is a current Fellow of the Leukemia and Lymphoma Society. K.K.K. is supported by the John Reed Fund of the MIT undergraduate research program. M.M.W. was a Merck Fellow of the Damon Runyon Cancer Research Foundation and a Genentech postdoctoral fellow. T.J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar. The Howard Hughes Medical Institute supported this work.

Author information

D.M.F. and T.J. conceived of the experiments and wrote the manuscript with comments from all authors; D.M.F., K.K.K, C.C., S.E.T. and R.R. performed the experiments and analysed the data; M.M.W. and F.J.S.-R. gave conceptual advice; R.B. performed histological evaluations; C.A.W. performed bioinformatics data analysis; and M.T.H. provided reagents and conceptual advice.

Correspondence to Tyler Jacks.

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The authors declare no competing financial interests.

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Gene expression data was deposited in Gene Expression Omnibus (GSE23875).

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Feldser, D., Kostova, K., Winslow, M. et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468, 572–575 (2010) doi:10.1038/nature09535

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