Hsp90 Inhibitor Ganetespib Sensitizes Non-Small Cell Lung Cancer to Radiation but Has Variable Effects with Chemoradiation.
Hsp90 Inhibitor Ganetespib Sensitizes Non-Small Cell Lung Cancer to Radiation but Has Variable Effects with Chemoradiation.
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DOI：
10.1158/1078-0432.ccr-15-2190
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发表时间：
2016-12-01
期刊：
影响因子：
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通讯作者：
Lin SH
中科院分区：
文献类型：
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作者：
Wang Y;Liu H;Diao L;Potter A;Zhang J;Qiao Y;Wang J;Proia DA;Tailor R;Komaki R;Lin SH
众所周知，HSP90 抑制会使癌细胞对辐射敏感。然而，目前尚不清楚在更具临床相关性的放化疗（CRT）中是否会发生额外的放射增敏。我们使用强效 HSP90 抑制剂 ganetespib 来确定它是否可以增强 NSCLC 中的 CRT 效果。我们首先在各种 NSCLC 细胞系中进行体外实验，结合放射治疗或不治疗 ganetespib。其中一些实验包括克隆存活测定、DNA 损伤修复和细胞周期分析以及反相蛋白阵列。然后，我们通过在一些体外和体内异种移植实验中添加卡铂-紫杉醇来确定化疗是否影响 ganetespib 放射增敏作用。 Ganetespib 显着降低了许多肺癌细胞系的辐射克隆存活率，并减弱了辐射造成的 DNA 损伤修复。辐射导致 G2/M 停滞，ganetespib 大大加剧了这种停滞。 Ganetespib 联合放射治疗还可以剂量依赖性上调 p21 水平并下调 pRb 水平，而单独使用药物或放射治疗时这种情况并不明显。然而，当添加卡铂-紫杉醇时，ganetepsib 只能使某些细胞系放射增敏，而不能使其他细胞系放射增敏。使用异种移植模型在体内证实了这种可变的体外 CRT 效应。 Ganetespib 能够有效地使许多 NSCLC 细胞系对辐射敏感，但当添加到基于铂的双峰 CRT 中时，会产生不同的效果。为了实现最佳临床转化，我们的数据强调了在临床相关治疗组合背景下进行药物临床前测试的重要性。
HSP90 inhibition is well known to sensitize cancer cells to radiation. However, it is currently unknown if additional radiosensitization could occur in the more clinically relevant setting of chemoradiation (CRT). We used the potent HSP90 inhibitor ganetespib to determine if it can enhance CRT effects in NSCLC. We first performed in vitro experiments in various NSCLC cell lines combining radiation with or without ganetespib. Some of these experiments included clonogenic survival assay, DNA damage repair and cell cycle analysis, and Reverse Phase Protein Array. We then determined if chemotherapy affected ganetespib radiosensitization by adding carboplatin-paclitaxel to some of the in vitro and in vivo xenograft experiments. Ganetespib significantly reduced radiation clonogenic survival in a number of lung cancer cell lines, and attenuated DNA damage repair with irradiation. Radiation caused G2/M arrest that was greatly accentuated by ganetespib. Ganetespib with radiation also dose-dependently up-regulated p21 and down-regulated pRb levels that were not apparent with either drug or radiation alone. However, when carboplatin-paclitaxel was added, ganetepsib was only able to radiosensitize some cell lines but not to others. This variable in vitro CRT effect was confirmed in vivo using xenograft models. Ganetespib was able to potently sensitize a number of NSCLC cell lines to radiation but has variable effects when added to platinum-based doublet CRT. For optimal clinical translation, our data emphasizes the importance of preclinical testing of drugs in the context of clinically-relevant therapy combinations.