Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen 37077, Germany.
Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
Cancer Cell. 2018 Aug 13;34(2):298-314.e7. doi: 10.1016/j.ccell.2018.07.004.
Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53) exerts gain of function (GOF) and creates tumor dependence in mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53 allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth. Importantly, human CRCs with stabilized mutp53 exhibit enhanced Jak2/Stat3 signaling and are associated with poorer patient survival. Cancers with TP53 are associated with a higher patient death risk than are those having nonR248 mutp53. These findings identify GOF mutp53 as a therapeutic target in CRC.
超过一半的结直肠癌（CRC）存在 TP53 错义突变（mutp53）。我们表明，最常见的 mutp53 等位基因 R248Q（p53）发挥获得性功能（GOF），并在小鼠 CRC 模型中产生肿瘤依赖性。mutp53 蛋白结合 Stat3 并通过置换磷酸酶 SHP2 增强激活 Stat3 的磷酸化。p53 等位基因的缺失抑制了 Jak2/Stat3 信号转导、生长和已建立的、mutp53 驱动的肿瘤的侵袭性。用 HSP90 抑制剂治疗荷瘤小鼠可抑制 mutp53 水平和肿瘤生长。重要的是，稳定 mutp53 的人 CRC 表现出增强的 Jak2/Stat3 信号，并且与患者生存较差相关。与非 R248 mutp53 相比，具有 TP53 的癌症与更高的患者死亡风险相关。这些发现确定了 GOF mutp53 是 CRC 的治疗靶点。
