Purpose/Objectives: Attempts at improving the outcome of colorectal cancer patients by incorporating novel agents have been disappointing indicating that in the majority of patients the therapeutic challenge remains primary resistance to chemoradiotherapy. Major cellular signaling pathways contributing to growth and resistance to chemoradiotherapy in rectal cancer includes the PI3K/AKT/NF-κB pathway. The heat shock protein 90 (HSP90) regulates the activity, turnover, and trafficking of several proteins involved in these pathways of resistance. Inhibition of HSP90 provides a novel mechanism to target these pathways simultaneously. Ganetespib (STA-9090) is a small molecule functional inhibitor of HSP90. We tested the hypothesis that HSP90 inhibition can sensitize colorectal cell lines to the effects of ionizing radiation (XRT). Methods: Immunohistochemical (IHC) analyses of 10 colorectal paired normal and tumor tissue samples from the same 10 patients were stained with antibodies against HSP90, HSP70, and p-AKT. Cell proliferation (XTT), colony formation (clonogenic assay), migration (spheroid), apoptosis (Apoptosis/Necrosis Detection Kit), and Western blot analyses were carried out in HCT-116 and HT-29 colorectal cell lines to determine the effect of ganetespib alone or in combination with XRT. Results: IHC analyses of paired human colorectal normal and tumor samples revealed significant overexpression of HSP90, HSP70, and p-AKT in the tumors when compared to the normal tissues. In both colorectal cell lines, treatment with ganetespib significantly inhibits proliferation in the XTT assay (p<0.001); significantly decreased expression of PI3K and p-AKT, as well as significantly increased levels of HSP70 in Western blot analyses (p<0.05); and inhibited the nuclear translocation (immunocyto studies) and the DNA binding activity (EMSA) of the NF-κB p65 molecules. We found that ganetespib indeed potentiates the effects of XRT in both cell lines: significant decrease in colony formation as determined by the clonogenic assay (p<0.001); increase in the induction of necrosis; and decreased migration. Conclusions: The HSP90 pathway is selectively activated in patient's rectal tumors and is a rational target for drug development. HSP90 inhibition potentiates the effects of ionizing radiation in preclinical models. Evaluating HSP90 inhibitors in rectal cancer is a rational approach that could have a significant impact on the outcome of this common and deadly disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2872. doi:1538-7445.AM2012-2872

©2012 American Association for Cancer Research
2012