p53 腫瘤抑制通道的失活是人類癌癥的一個(gè)普遍特征，所以人們便想,，恢復(fù)已形成的腫瘤中的p53 功能也許會(huì)是一種有效療法,。然而，本期Nature上兩篇論文突顯了以p53為方向的癌癥療法在實(shí)踐上的局限性,。
他們?cè)谝粋€(gè)K-Ras-driven肺癌模型中發(fā)現(xiàn),，由p53調(diào)控的腫瘤抑制只在腫瘤發(fā)展的后期階段才發(fā)揮作用，這個(gè)時(shí)候K-Ras致癌信號(hào)已達(dá)到足以激活A(yù)RF-p53通道的閾限,。這意味著p53的重新表達(dá)未能抑制腫瘤發(fā)生的早期階段,，盡管它的確誘導(dǎo)了更為激進(jìn)的腫瘤的退行。（生 物 谷Bioon.com）
生 物 谷推薦英文摘要：
Nature doi:10.1038/nature09526
Selective activation of p53-mediated tumour suppression in high-grade tumours
Melissa R. Junttila,Anthony N. Karnezis,Daniel Garcia,Francesc Madriles,Roderik M. Kortlever,Fanya Rostker,Lamorna Brown Swigart,David M. Pham,Youngho Seo,Gerard I. [email protected]& Carla P. Martins
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 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.
