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Abstract

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, 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.

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.​ 

Author information​

Wang Y1,2, Liu H1, Diao L3, Potter A4, Zhang J1, Qiao Y1, Wang J3, Proia DA5, Tailor R6, Komaki R7, Lin SH8,7.

1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

2The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.

3Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

4Texas A&M School of Medicine, College Station, Texas.

5Synta Pharmaceuticals Corp, Lexington, Massachusetts.

6Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

7Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

8Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. shlin@mdanderson.org.