Implementing targeted drug therapy in radio-oncologic treatment regimens has greatly improved the outcome of cancer patients. However, the efficacy of molecular targeted drugs such as inhibitory antibodies or small molecule inhibitors essentially depends on target expression and activity, which both can change during the course of treatment. Radiotherapy has previously been shown to activate prosurvival pathways, which can help tumor cells to adapt and thereby survive treatment. Therefore, we aimed to identify changes in signaling induced by radiation and evaluate the potential of targeting these changes with small molecules to increase the therapeutic efficacy on cancer cell survival. Analysis of “The Cancer Genome Atlas” database disclosed a significant overexpression of AKT1, AKT2, and MTOR genes in human prostate cancer samples compared with normal prostate gland tissue. Multifractionated radiation of three-dimensional–cultured prostate cancer cell lines with a dose of 2 Gy/day as a clinically relevant schedule resulted in an increased protein phosphorylation and enhanced protein–protein interaction between AKT and mTOR, whereas gene expression of AKT, MTOR, and related kinases was not altered by radiation. Similar results were found in a xenograft model of prostate cancer. Pharmacologic inhibition of mTOR/AKT signaling after activation by multifractionated radiation was more effective than treatment prior to radiotherapy. Taken together, our findings provide a proof-of-concept that targeting signaling molecules after activation by radiotherapy may be a novel and promising treatment strategy for cancers treated with multifractionated radiation regimens such as prostate cancer to increase the sensitivity of tumor cells to molecular targeted drugs. Mol Cancer Ther; 17(2); 355–67. ©2017 AACR. See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”

中文翻译：

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利用辐射诱导的信号传导来增加耐药癌细胞对靶向药物的敏感性：以 AKT 和 mTOR 抑制剂为例


在放射肿瘤治疗方案中实施靶向药物治疗极大地改善了癌症患者的预后。然而，抑制性抗体或小分子抑制剂等分子靶向药物的疗效本质上取决于靶标的表达和活性，而这两者都可能在治疗过程中发生变化。此前，放射治疗已被证明可以激活促存活途径，从而帮助肿瘤细胞适应并从而在治疗中存活下来。因此，我们的目的是确定辐射引起的信号传导变化，并评估用小分子靶向这些变化以提高癌细胞存活治疗效果的潜力。对“癌症基因组图谱”数据库的分析显示，与正常前列腺组织相比，人类前列腺癌样本中 AKT1、AKT2 和 MTOR 基因显着过度表达。作为临床相关方案，对三维培养的前列腺癌细胞系进行 2 Gy/天剂量的多次分割辐射，导致蛋白质磷酸化增加，AKT 和 mTOR 之间的蛋白质-蛋白质相互作用增强，而 AKT、MTOR、相关激酶不会因辐射而改变。在前列腺癌的异种移植模型中也发现了类似的结果。多分割放射激活后对 mTOR/AKT 信号传导的药物抑制比放射治疗前的治疗更有效。总而言之，我们的研究结果提供了一个概念证明，即通过放射疗法激活后靶向信号分子可能是一种新颖且有前途的治疗策略，对于采用多分割放射治疗方案（例如前列腺癌）治疗的癌症来说，可以提高肿瘤细胞对分子靶向药物的敏感性。 摩尔癌症治疗； 17(2)； 355–67。 ©2017 AACR。请参阅此 MCT 焦点部分中的所有文章“放射肿瘤学中的发育治疗”。”