Clinical Cooperation Unit Neurooncology, German Cancer Research Center DKFZ, Heidelberg, Germany.
Oncogene. 2013 Feb 28;32(9):1099-109. doi: 10.1038/onc.2012.137. Epub 2012 May 7.
An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.
一种获得性抵抗放疗（RT）的基本模式似乎是促进各种癌症类型的肿瘤细胞运动和侵袭，包括神经胶质瘤，这一过程类似于“逃避性抵抗”。因此，RT 的一个合理进展将是确定合适的补充治疗策略，理想情况下是针对细胞运动。在这里，我们报告说，使用临床相关浓度的雷帕霉素（CCI-779）的局部 RT 和哺乳动物雷帕霉素靶蛋白（mTOR）抑制的组合，通过附加的细胞抑制作用，延长了同源小鼠神经胶质瘤模型的存活时间。在体外，mTOR 抑制剂 CCI-779 表现出明显的抗侵袭作用，而与磷酸酶和张力蛋白同源物缺失的染色体 10 状态无关，并抵消了亚致死辐射的促侵袭作用。从机制上讲，我们确定了 G 蛋白信号调节因子 4（RGS4）作为 mTOR 抑制的一个新靶点和神经胶质瘤侵袭的关键驱动因素，对 CCI-779 的抗侵袭特性敏感。值得注意的是，RGS4 依赖性神经胶质瘤细胞侵袭的抑制信号通过 mTORC1 和 mTORC2 两种 mTOR 复合物以浓度依赖性方式发出，表明高剂量的 CCI-779 可能克服与仅抑制 mTORC1 相关的肿瘤细胞耐药性。我们得出结论，联合 RT 和 mTOR 抑制是一种很有前途的治疗选择，值得在胶质母细胞瘤的初始治疗中进一步进行临床研究。
