p53 肿瘤抑制通道的失活是人类癌症的一个普遍特征，所以人们便想，恢复已形成的肿瘤中的p53 功能也许会是一种有效疗法。然而，本期Nature上两篇论文突显了以p53为方向的癌症疗法在实践上的局限性。
他们在一个K-Ras-driven肺癌模型中发现，由p53调控的肿瘤抑制只在肿瘤发展的后期阶段才发挥作用，这个时候K-Ras致癌信号已达到足以激活ARF-p53通道的阈限。这意味着p53的重新表达未能抑制肿瘤发生的早期阶段，尽管它的确诱导了更为激进的肿瘤的退行。（生 物 谷Bioon.com）
生 物 谷推荐英文摘要：
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. Evangie20@cam.ac.uk& 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.
