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posted on 2023-03-31, 18:43 authored by Yifan Wang, Hui Liu, Lixia Diao, Adam Potter, Jianhu Zhang, Yawei Qiao, Jing Wang, David A. Proia, Ramesh Tailor, Ritsuko Komaki, Steven H. Lin Supplemental Figure 1. RPPA heat map of H460 cells treated with varying doses of radiation and ganetespib. Supplemental Figure 2. RPPA heat map of A549 cells treated with varying doses of radiation and ganetespib. Supplemental Figure 3. Western blot validation of some of the altered proteins seen on RPPA analysis in H460 cells. Supplemental Figure 4. The apoptosis indicated by Caspase cleavage in RPPA and western blot were confirmed by flow cytometry Annexin V analysis. Supplemental Figure 5. H460 xenograft recapitulated in vitro DNA damage and apoptosis results.
Funding
The Mabuchi Program in Targeted Radiotherapy
United Against Lung Cancer
The University of Texas MD Anderson Cancer Center
National Cancer Institute Cancer Center
History
ARTICLE 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. Clin Cancer Res; 22(23); 5876–86. ©2016 AACR.
