Wang Yifan, Liu Hui, Diao Lixia, Potter Adam, Zhang Jianhu, Qiao Yawei, Wang Jing, Proia David A, Tailor Ramesh, Komaki Ritsuko, Lin Steven H
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
Clin Cancer Res. 2016 Dec 1;22(23):5876-5886. doi: 10.1158/1078-0432.CCR-15-2190. Epub 2016 Jun 28.
HSP90 inhibition is well known to sensitize cancer cells to radiation. However, it is currently unknown whether additional radiosensitization could occur in the more clinically relevant setting of chemoradiation (CRT). We used the potent HSP90 inhibitor ganetespib to determine whether 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 whether 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 G-M arrest that was greatly accentuated by ganetespib. Ganetespib with radiation also dose-dependently upregulated p21 and downregulated pRb levels that were not apparent with either drug or radiation alone. However, when carboplatin-paclitaxel was added, ganetespib was only able to radiosensitize some cell lines but not 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 emphasize the importance of preclinical testing of drugs in the context of clinically relevant therapy combinations. Clin Cancer Res; 22(23); 5876-86. ©2016 AACR.
众所周知，HSP90抑制可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）环境中是否会发生额外的放射增敏作用。我们使用强效HSP90抑制剂ganetespib来确定它是否能增强非小细胞肺癌（NSCLC）的CRT效果。
我们首先在各种NSCLC细胞系中进行体外实验，将辐射与有或没有ganetespib的情况相结合。其中一些实验包括克隆形成存活测定、DNA损伤修复和细胞周期分析，以及反向蛋白质阵列分析。然后，我们通过在一些体外和体内异种移植实验中加入卡铂-紫杉醇，来确定化疗是否会影响ganetespib的放射增敏作用。
Ganetespib显著降低了多种肺癌细胞系的辐射克隆形成存活率，并减弱了辐射引起的DNA损伤修复。辐射导致G-M期阻滞，而ganetespib大大加剧了这种阻滞。Ganetespib与辐射联合使用还剂量依赖性地上调p21并下调pRb水平，这在单独使用药物或辐射时并不明显。然而，当加入卡铂-紫杉醇时，ganetespib仅能使某些细胞系对辐射敏感，而对其他细胞系则不然。这种体外CRT效果的差异在体内异种移植模型中得到了证实。
Ganetespib能够有效地使多种NSCLC细胞系对辐射敏感，但在加入基于铂的双药CRT时效果存在差异。为了实现最佳的临床转化，我们的数据强调了在临床相关治疗组合的背景下对药物进行临床前测试的重要性。《临床癌症研究》；22(23)；5876 - 86。©2016美国癌症研究协会。
