TY - JOUR
T1 - Hsp90 inhibitor ganetespib sensitizes non-small cell lung cancer to radiation but has variable effects with chemoradiation
AU - Wang, Yifan
AU - Liu, Hui
AU - Diao, Lixia
AU - Potter, Adam
AU - Zhang, Jianhu
AU - Qiao, Yawei
AU - Wang, Jing
AU - Proia, David A.
AU - Tailor, Ramesh
AU - Komaki, Ritsuko
AU - Lin, Steven H.
N1 - Publisher Copyright:
©2016 AACR.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Purpose: 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. Experimental Design: 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,DNAdamage 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. Results: 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 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. Conclusions: 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.
AB - Purpose: 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. Experimental Design: 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,DNAdamage 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. Results: 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 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. Conclusions: 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.
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U2 - 10.1158/1078-0432.CCR-15-2190
DO - 10.1158/1078-0432.CCR-15-2190
M3 - Article
C2 - 27354472
AN - SCOPUS:85006272671
SN - 1078-0432
VL - 22
SP - 5876
EP - 5886
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -