Selective activation of p53-mediated tumour suppression in high-grade tumours

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%. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras. p53 is also frequently inactivated...

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Bibliographic Details
Published in:Nature (London) 2010-11, Vol.468 (7323), p.567-571
Main Authors: Rostker, Fanya, Junttila, Melissa R, Kortlever, Roderik M, Evan, Gerard I, Seo, Youngho, Martins, Carla P, Garcia, Daniel, Madriles, Francesc, Brown Swigart, Lamorna, Karnezis, Anthony N, Pham, David M
Format: Article
Language:English
Subjects:
Animal tumors. Experimental tumors
Animals
Biological and medical sciences
Carcinoma, Non-Small-Cell Lung - metabolism
Carcinoma, Non-Small-Cell Lung - physiopathology
Cell Proliferation
Development and progression
Disease Models, Animal
Experimental respiratory system tumors
Gene expression
Gene Expression Regulation, Neoplastic
Identification and classification
Lung cancer
Lung cancer, Non-small cell
Lung Neoplasms - metabolism
Lung Neoplasms - physiopathology
Medical sciences
Mice
Mutation
Oncology
Pharmacology
Physiological aspects
Properties
Proto-Oncogene Proteins p21(ras) - metabolism
ras Proteins - metabolism
Tumor proteins
Tumor suppressor genes
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Tumors
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Summary: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%. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras. 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 disease. 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 Kras. 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 p19ARF (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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature09526