Exploiting Radiation-Induced Signaling to Increase the Susceptibility of Resistant Cancer Cells to Targeted Drugs: AKT and mTOR Inhibitors as an Example.
Exploiting Radiation-Induced Signaling to Increase the Susceptibility of Resistant Cancer Cells to Targeted Drugs: AKT and mTOR Inhibitors as an Example.
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DOI：
10.1158/1535-7163.mct-17-0262
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发表时间：
2018-03
影响因子：
5.7
通讯作者：
Coleman CN
中科院分区：
文献类型：
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作者：
Eke I;Makinde AY;Aryankalayil MJ;Sandfort V;Palayoor ST;Rath BH;Liotta L;Pierobon M;Petricoin EF;Brown MF;Stommel JM;Ahmed MM;Coleman CN
在放射肿瘤治疗方案中实施靶向药物治疗大大改善了癌症患者的预后。然而，诸如抑制性抗体或小分子抑制剂的分子靶向药物的功效基本上取决于靶标表达和活性，这两者都可以在治疗过程中改变。放射治疗以前已被证明可以激活促生存途径，这可以帮助肿瘤细胞适应，从而在治疗中存活。因此，我们的目的是确定辐射诱导的信号传导的变化，并评估用小分子靶向这些变化以提高对癌细胞存活的治疗效果的潜力。对“癌症基因组图谱”（TCGA）数据库的分析揭示了与正常前列腺组织相比，人类前列腺癌样品中AKT 1、AKT 2和MTOR基因的显著过表达。以2戈伊/天的剂量作为临床相关时间表对3D培养的前列腺癌细胞系进行多分割辐射，导致蛋白磷酸化增加以及AKT和mTOR之间的蛋白-蛋白相互作用增强，而AKT、MTOR和相关激酶的基因表达未被辐射改变。在前列腺癌异种移植模型中也发现了类似的结果。多分割放射激活后的mTOR/AKT信号传导的药理学抑制比放射治疗前的治疗更有效。综上所述，我们的研究结果提供了一个概念验证，即通过放射治疗激活后靶向信号分子可能是一种新的和有前途的治疗策略，用于用多分割放射方案治疗的癌症，如前列腺癌，以增加肿瘤细胞对分子靶向药物的敏感性。
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 pro-survival 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” (TCGA) 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 3D-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, while gene expression of AKT, MTOR, and related kinases was not altered by radiation. Similar results were found in a xenograft model of prostate cancer. Pharmacological 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.