Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10–15%1. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras2. p53 is also frequently inactivated in NSCLC and, because oncogenic Ras can be a potent trigger of p53 (ref. 3), it seems likely that oncogenic Ras signalling has a major and persistent role in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease4. Here we model the probable therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras5. Surprisingly, p53 restoration failed to induce significant regression of established tumours, although it did result in a significant decrease in the relative proportion of high-grade tumours. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signalling sensor p19 ARF(ref. 6). Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.
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We are indebted to T. Jacks for the KR mice, C. Sherr and M. Roussel for the p19 ARF antibody, M. Dail and A.-T. Maia for advice on Kras copy number analysis and V. Weinberg for guidance on statistical analysis. We also thank D. Tuveson and all the members of the Evan laboratory for their comments. This work was supported by grants NCI CA98018, NCI CA100193, AICR 09-0649, the Ellison Medical Foundation and from the Samuel R. Waxman Cancer Research Foundation (all to G.I.E.). M.R.J. is the Enrique Cepero, PhD Fellow of the Damon Runyon Cancer Research Foundation.
The authors declare no competing financial interests.
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Junttila, M., Karnezis, A., Garcia, D. et al. Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 468, 567–571 (2010) doi:10.1038/nature09526
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