Department of Radiation Oncology Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232-5671, USA.
J Thorac Oncol. 2011 Apr;6(4):699-706. doi: 10.1097/JTO.0b013e31820d9d11.
Persistent STAT3 activation contributes to lung carcinogenesis. Survivin, one of STAT3-regulated genes, is antiapoptotic and confers cancer radioresistance.
We tested whether TG101209, a small-molecule inhibitor of JAK2 (a STAT3-activating tyrosine kinase), affected survivin expression and sensitized lung cancer to radiation. We investigated whether inhibition of JAK2 signaling with TG101209 can be used to reduce survivin expression and enhance radiosensitivity of lung cancer cells in vitro and tumor growth delay in vivo. JAK2 downstream signaling, including PI3-K/Akt and Ras/MAPK/ERK pathways, was also explored.
TG101209 inhibited STAT3 activation and survivin expression and sensitized HCC2429 (dose enhancement ratio = 1.34, p = 0.002) and H460 (dose enhancement ratio = 1.09, p = 0.006) cells to radiation in clonogenic assays. Radiation promoted phospho-Akt and phospho-ERK in H460 cells, while their levels were unchanged in HCC2429. After treatment with TG101209, phospho-ERK protein levels were reduced in both HCC2429 and H460 cells. HCC2429 cells transfected with KRAS-12V mutant were more resistant to radiation- and TG101209-induced apoptosis than wild-type control cells. In vivo, addition of TG101209 to radiation in lung xenografts produced a significant tumor growth delay (>10 days) compared with radiation alone and was well tolerated. Immunohistochemistry staining of tumor sections showed that TG101209 increased apoptosis and decreased cell proliferation and vascular density, suggesting that TG101209 also has antiangiogenic effects.
TG101209 enhanced the effects of radiation in lung cancer in vitro and in vivo. This study suggests the potential utility of selecting lung cancer patients according to KRAS mutation status for future clinical trials testing combination of TG101209 and radiotherapy.
持续的 STAT3 激活有助于肺癌的发生。Survivin 是 STAT3 调控的基因之一，具有抗凋亡作用，并赋予癌症放射抗性。
我们测试了小分子 JAK2（STAT3 激活的酪氨酸激酶）抑制剂 TG101209 是否会影响 survivin 的表达，并使肺癌对辐射敏感。我们研究了在体外使用 TG101209 抑制 JAK2 信号是否可以减少 survivin 的表达并增强肺癌细胞的放射敏感性，以及体内肿瘤生长的延迟。还探讨了 JAK2 下游信号，包括 PI3-K/Akt 和 Ras/MAPK/ERK 通路。
TG101209 抑制了 HCC2429（剂量增强比 = 1.34，p = 0.002）和 H460（剂量增强比 = 1.09，p = 0.006）细胞的 STAT3 激活和 survivin 表达，并使它们对克隆形成分析中的辐射敏感。辐射促进了 H460 细胞中磷酸化 Akt 和磷酸化 ERK 的表达，而 HCC2429 细胞中的这些蛋白水平不变。用 TG101209 处理后，两种 HCC2429 和 H460 细胞中的磷酸化 ERK 蛋白水平均降低。与野生型对照细胞相比，转染 KRAS-12V 突变的 HCC2429 细胞对辐射和 TG101209 诱导的细胞凋亡更具抗性。在体内，与单独放疗相比，将 TG101209 加入到肺异种移植瘤中可显著延迟肿瘤生长（>10 天），且耐受性良好。肿瘤切片的免疫组织化学染色显示，TG101209 增加了凋亡，减少了细胞增殖和血管密度，这表明 TG101209 还具有抗血管生成作用。
TG101209 增强了肺癌在体外和体内的放射作用。这项研究表明，根据 KRAS 突变状态选择肺癌患者进行未来的临床试验，测试 TG101209 与放疗的联合应用具有潜在的应用价值。
