Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term TβRI/II kinase inhibition with LY2109761.
Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term TβRI/II kinase inhibition with LY2109761.
复制标题
DOI：
10.1158/0008-5472.can-10-2941
复制
发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Akhurst RJ
中科院分区：
文献类型：
--
作者：
Connolly EC;Saunier EF;Quigley D;Luu MT;De Sapio A;Hann B;Yingling JM;Akhurst RJ
转化生长因子β (TGF-β)在许多实体肿瘤中过量产生，可通过对肿瘤细胞和微环境的多重作用驱动恶性进展。TGF-β信号通路抑制剂在转移性癌症的临床前模型中显示出疗效。本文研究了I/ II型受体（TβRI/TβRII）激酶抑制剂LY2109761在异体肿瘤移植模型和体内化学诱导的小鼠皮肤新发癌变模型中的作用。LY2109761系统给药可破坏肿瘤血管结构，降低异体肿瘤移植中E4皮肤癌细胞的肌成纤维细胞分化。在7、12二甲基苯并蒽加磷酸肉豆酸酯诱导的皮肤化学癌变模型中，LY2109761 （100mg/Kg）每8小时急性给药10天（100mg/Kg）可降低P-Smad2水平，并轻微降低炎症和侵袭性标志物的表达。在整个肿瘤生长阶段持续暴露于LY2109761 （100mg/kg/天）对癌症潜伏期或发病率没有影响。然而，通过微阵列基因表达、Western blot和免疫组织化学对所产生的肿瘤进行分子分析表明，长期暴露于LY2109761可导致P-Smad2水平升高的肿瘤生长，且对药物无反应。这是对TGF-βRI/II激酶小分子抑制剂获得性耐药的首次描述。由此产生的癌在本质上更具侵袭性和炎症性，E-Cadherin脱位，Il23a、层粘连蛋白V和MMPs的表达升高。因此，TGF-β抑制剂可能在临床上对需要急性给药的应用有用，但慢性患者暴露于此类药物时应谨慎。
Transforming Growth Factor β (TGF-β) is produced excessively by many solid tumors and can drive malignant progression through multiple effects on the tumor cell and microenvironment. TGF-β signaling pathway inhibitors have shown efficacy in pre-clinical models of metastatic cancer. Here we investigated the effect of systemic LY2109761, a type I /II receptor (TβRI/TβRII) kinase inhibitor, in both a tumor allograft model and in the mouse skin model of de novo chemically-induced carcinogenesis in vivo. Systemic LY2109761 administration disrupted tumor vascular architecture and reduced myofibroblast differentiation of E4 skin carcinoma cells in a tumor allograft. In the 7,12 dimethyl-benzanthracene plus phorbol-myristate-acetate -induced skin chemical carcinogenesis model, acute dosing of established naïve primary carcinomas with LY2109761 (100mg/Kg) every eight hours for ten days (100mg/kg) diminished P-Smad2 levels and marginally decreased the expression of inflammatory and invasive markers. Sustained exposure to LY2109761 (100mg/kg/day) throughout the tumor outgrowth phase had no effect on carcinoma latency or incidence. However, molecular analysis of resultant carcinomas by microarray gene expression, Western blot and immunohistochemistry suggests that long term LY2109761 exposure leads to the outgrowth of carcinomas with elevated P-Smad2 levels that do not respond to drug. This is the first description of acquired resistance to a small molecule inhibitor of the TGF-βRI/II kinase. Resultant carcinomas were more aggressive and inflammatory in nature, with delocalized E-Cadherin and elevated expression of Il23a, laminin V and MMPs. Therefore, TGF-β inhibitors might be clinically useful for applications requiring acute administration, but chronic patient exposure to such drugs should be undertaken with caution.