Modeling the Therapeutic Efficacy of p53 Restoration in Tumors
Carla P. Martins,1 Lamorna Brown-Swigart,1 and Gerard I. Evan1,

1 Cancer Research Institute and Department of Cellular and Molecular Pharmacology, Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA

Corresponding author
Gerard I. Evan
gevan@cc.ucsf.edu

Summary

Although restoration of p53 function is an attractive tumor-specific therapeutic strategy, it remains unclear whether p53 loss is required only for transition through early bottlenecks in tumorigenesis or also for maintenance of established tumors. To explore the efficacy of p53 reinstatement as a tumor therapy, we used a reversibly switchable p53 knockin (KI) mouse model that permits modulation of p53 status from wild-type to knockout, at will. Using the well-characterized Eμ-myc lymphoma model, we show that p53 is spontaneously activated when restored in established Eμ-myc lymphomas in vivo, triggering rapid apoptosis and conferring a significant increase in survival. Nonetheless, reimposition of p53 function potently selects for emergence of p53-resistant tumors through inactivation of p19ARF or p53. Our study provides important insights into the nature and timing of p53-activating signals in established tumors and how resistance to p53 evolves, which will aid in the optimization of p53-based tumor therapies.

虽然恢复p53功能相当有吸引力肿瘤特异性治疗策略 p53的损失仍不清楚只需要通过转型瓶颈肿瘤早期或肿瘤还设立维修. 探索功效职权作为肿瘤治疗中p53、 我们用p53的可逆切换敲入小鼠模型(棋),从野生状态中P53许可证调制型向淘汰, 浏览. 用好特点eμ义淋巴瘤模型 我们表明p53的激活是自发成立时恢复eμ义体内淋巴瘤、 快速触发凋亡和授予大增生存. 尽管如此,二度p53的细胞具有选择功能的出现,为p53的抗肿瘤经过灭活p19arf或p53. 我们的研究提供了重要的洞察力的性质和时间中P53活化信号,以及如何建立抗肿瘤p53的演变, 这将有助于优化中P53型肿瘤疗法.