The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Selective activation of p53-mediated tumour suppression in high-grade tumours
Open accessAbstract
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.
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Cites
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
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Self-citationDose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis
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The pathological response to DNA damage does not contribute to p53-mediated tumour suppression
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Cited by
How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression
Aubrey, B. J., Kelly, G. L., Janic, A., Herold, M. J., & Strasser, A. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.169 · Cited by 1,395
P53 in survival, death and metabolic health: a lifeguard with a licence to kill.
Kruiswijk, F., Labuschagne, C. F., & Vousden, K. H. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4007 · Cited by 1,080
Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy
Skoulidis, F., & Heymach, J. V. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0179-8 · Cited by 1,019
Senescence and aging: the critical roles of p53
Rufini, A., Tucci, P., Celardo, I., & Melino, G. (2013) · Oncogene · doi:10.1038/onc.2012.640 · Cited by 798
The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance
Bouwman, P., & Jonkers, J. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3342 · Cited by 615
Metadata
- Authors
- Junttila, M. R., Karnezis, A. N., Garcia, D., Madriles, F., Kortlever, R. M., Rostker, F., Brown Swigart, L., Pham, D. M., Seo, Y., Evan, G. I., & Martins, C. P.
- Venue
- Nature
- Published
- 2010-11
- Volume
- 468
- Issue
- 7323
- Pages
- 567-571
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1973748124
- Cited by
- 245
- References
- 11
- FWCI
- 11.11
- Type
- journal article
- Language
- en
- Open access
- green
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- Junttila, M. R., Karnezis, A. N., Garcia, D., Madriles, F., Kortlever, R. M., Rostker, F., Brown Swigart, L., Pham, D. M., Seo, Y., Evan, G. I., & Martins, C. P. (2010). Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature. https://doi.org/10.1038/nature09526
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