Abstract 4894: The HSP90 inhibitor ganetespib potentiates effect of ionizing radiation in human non-small cell lung cancer

Abstract

Abstract Background: Ionizing irradiation (IR) is used to treat NSCLC however; radiotherapy remains largely palliative due to radioresistance. Recently, we reported that IR-resistant residual cells in NSCLC expresses a complex phenotype combining cancer stem cell (CSC) and the epithelial to mesenchymal transition (EMT) traits. The tyrosine kinase receptors (RTK) receptors, such as PDGFRa, EGFR FGFR and VEGFR, are expressed in nonrelated cells and IR-resistant residual cells. Moreover, PDGFRb is dramatically upregulated in IR resistant cells. Since all of these RTK receptors, as well as other oncogenic proteins are client proteins of the molecular chaperone HSP90a, NSCLC cells and specifically IR-resistant residual cells could be highly dependent on HSP90 and sensitive to HSP90 inhibition. We hypothesize that inhibition of HSP90 will eliminate IR-resistant residual cells and sensitize NSCLC cells to IR treatment. Methods/Results: HSP90 inhibitor Ganetespib, kindly provided by SYNTA Pharmaceuticals, was used in this study. A549 cells, primary human adenocarcinoma cells and primary normal human airway epithelial (HSAEC), were utilized. Using MTT and clonogenic assays we have demonstrated that ganetespib does not affect primary normal HSAEC cells, but suppresses the proliferation of NSCLC cells and potentiates the effect of IR treatment. Ganetespib inhibits the growth of lung tumor spheres. Using a wound healing assay we have determined that ganetespib inhibits motility of NSCLC cells and IR-resistant residual cells. We also have investigated the effect of ganetespib on cells cycle, apoptosis and DNA repair machinery in irradiated cells. Using a SCID mice model, we have demonstrated that ganetespib applied as monotherapy inhibits the growth of T2821 primary adenocarcinoma cells in vivo and significantly sensitizes T2821 tumors to IR-treatment. Conclusion: The HSP90 inhibitor ganetespib potentiates the effect of IR in NSCLC and eliminates IR-resistant residual cells. Note: This abstract was not presented at the meeting. Citation Format: Roberto Gomez Casal, Chitralekha Bhattacharya, Michael Epperly, Mark Socinski, Vera Levina. The HSP90 inhibitor ganetespib potentiates effect of ionizing radiation in human non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4894. doi:10.1158/1538-7445.AM2014-4894