Abstract A64: Targeting HSP90 with ganetespib for targeted therapy of gastric cancer

Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, due to its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib dramatically reduced growth of MGC-803 and also significantly inhibited growth of SGC-7901 and MKN-28 in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all three cell lines, together with the related markers affected significantly. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. Specifically, it greatly affected EGFR signaling cascades by dramatically decreasing levels of total EGFR and EGFR on cell membranes. EGFR knockdown also induced cell-cycle arrest and apoptosis accompanied with a decrease of several EGFR downstream proteins. These results strongly support EGFR signaling greatly contributes to the ganetespib inhibitory effects. Besides, we found the responses of GC cell lines to ganetespib correlated well with their EGFR expression levels: MGC-803, as well as AGS and BGC-803, with higher EGFR expression responded to ganetespib better, while SGC-7901 and MKN-28 with lower EGFR levels were much less sensitive to ganetespib. Though SGC-7901 and MKN-28 were not very sensitive to ganetespib, ganetespib worked synergistically with radiation and cisplatin in killing them. Importantly, ganetespib significantly inhibited growth of xenograft tumors in vivo as a single agent or in combination with cisplatin. Results of H&E staining, TUNEL assays, and immunohistochemistry staining of pCDK1, EGFR, and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR. Acknowledgments: This work was supported by the Jiangsu Specially-Appointed Professor Program (to H. Liu); Jiangsu Recruitment Program of Leading Creative and Entrepreneurial Talents (to H. Liu and Z. Tu); National Natural Science Foundation 81402145 (to H. Liu) and 31471294 (to Z. Tu); Natural Science Foundation of Jiangsu Province BK20140572 (to H. Liu); Start-up Scientific Resea