Antitumor activity of NVP-AUY922, a novel heat shock protein 90 inhibitor, in human gastric cancer cells is mediated through proteasomal degradation of client proteins

Abstract

Heat shock protein 90 (HSP90) is a molecular chaperone required for the stability of key regulators of cell survival and is an emerging target of cancer therapy. NVP-AUY922, a novel and potent inhibitor of HSP90, was evaluated against gastric cancer cell lines. NVP-AUY922 significantly inhibited the proliferation of all tested gastric cancer cell lines with 50% inhibitory concentration in the range of 2-40 nM and potently induced the degradation of growth factor receptors and other client proteins including HER-2, Akt and thymidylate synthase. HSP70 was induced by NVP-AUY922 and its binding with client proteins led to their proteasomal degradation. Moreover, the combination of NVP-AUY922 with cytotoxic chemotherapeutic agents such as 5-fluorouracil and oxaliplatin created a synergistic effect. Taken together, these preclinical data demonstrate the potent activity of NVP-AUY922 against gastric cancer cells and offer a rationale for clinical development of the agent alone or in combination with other chemotherapeutic drugs to effectively treat gastric cancer. (Cancer Sci 2011; 102: 1388-1395)