Search

been linked to more aggressive disease and poor clinical outcomes. HER2 is particularly reliant on the chaperoning activity of heat shock protein 90 (HSP90) for its stability and function. Pharmacological blockade of HSP90 results in cellular depletion and loss of its client proteins, in turn providing a means to simultaneously disrupt multiple oncogenic pathways. Ganetespib is a clinically advanced small molecule inhibitor of HSP90. Here, we have evaluated the antitumor activity and efficacy of ganetespib, both as a single agent and in combination with clinically approved drugs, in models of human gastric cancer. Material and Methods: Cell viability was determined by CellTiterGlo. The anticancer effect of ganetespib as single agent or coupled with other chemotherapeutic agents was examined via immunoblot, immunofluorescence, flow cytometry and xenograft models in SCID mice. Results: Ganetespib demonstrated potent in vitro cytotoxic activity in a panel of 22 gastric cancer cell lines in vitro, with an average IC50 value 20 nM. The panel included 3 HER2-overexpressing (HER2+) lines and antiproliferative activity was independent of p53 status. At the molecular level, ganetespib treatment promoted destabilization of multiple HSP90 client proteins and effectors, including HER2, EGFR, IGF-IR, cMET, cKit, P-AKT, P-ERK1/2 and a number of cell cycle modulators, which ultimately resulted in apoptosis. These effects of ganetespib were durable, with kinetic analysis showing client suppression was maintained for over 48 hours following a 1 hour drug exposure. Combinations of ganetespib with chemotherapeutic agents (doxorubicin, docetaxel, cisplatin) as well as the dual HER2/EGFR kinase inhibitor lapatinib promoted significant increases in total cell death in comparison to monotherapy. Synergistic effects were also observed when ganetespib was combined with the PI3K/mTOR inhibitor BEZ235, due in part to ganetespibs’ ability to overcome the rebound in AKT activity that arises from PI3K/mTOR inhibition. The combinatorial benefit observed in vitro translated to improved efficacy in vivo, where combinations of ganetespib with capecitabine or docetaxel induced tumor regressions in NCI-N87 xenografts. Conclusions: Taken together, these data highlight the potent antitumor activity of ganetespib for gastric cancer cells, including HER2+ lines, both in vitro and in animal models. The findings support the potential therapeutic value of ganetespib, particularly in combination with standardof-care agents, for the treatment of patients with gastric cancer.