Abstract 2767: AUY922, a heat shock protein 90 inhibitor, plus 5-fluorouracil inhibits tumors synergistically in gastric cancer MKN45 xenograft via down regulation of multiple pivotal growth factor receptors and oncoproteins

Abstract

Abstract Heat shock protein 90 (Hsp90) is the most abundant cellular chaperone and has nearly 100 pivotal client proteins, which are commonly dysregulated in cancers. The positive rate of Hsp90beta in gastric cancer (GC) tissue was approximately 30%, and was higher than non-cancerous gastric mucosa. Hsp90 inhibitors should have great potentials in the exploration for treatment strategy in gastric cancer (GC). NYP-AUY922-AG (AUY922), kindly provided by Novartis Pharma AG, is a novel resorcinylic isoxazole amide Hsp90 inhibitor. Using 72-hour MTT colorimetric assay, we have demonstrated that AUY922 has highly active growth inhibitory effects as a single agent of IC50 in the nanomolar ranges between 8.1 ± 0.2 and 14.7 ± 0.8 nM in the gastric cancer cell line panels (except c-met-overexpressing KATO-III cells with a IC50 of 158.1 ± 5.1 nM). In the gastric cancer MKN45 xenograft model, MKN45 cells (2 × 106) were injected subcutaneously in 100 αl of Matrigel/Hanks’ balanced salt solution to the flank of nude mice. AUY922 50 mg/kgw and 100 mg/kgw intraperitoneal weekly injection (i.p.) were used. Tumor inhibitory effects of AUY922 in the MKN45 human gastric cancer xenograft model were statistically evident in a dose-dependent and time-dependent manner. Several important growth factor receptors are overexpressed in GC, namely EGFR (epidermal growth factor receptor, HER1), HER-2/neu, and c-met (hepatocyte growth factor receptor, HGF receptor), etc. By immunohistochemical staining of xenograft tumor tissues using specific antibodies, AUY922 100 mg/kgw i.p. weekly significantly down regulates multiple growth factor receptors and oncoproteins, including c-met, HER-2/neu, IGF1-R, EGFR, Akt, and notably thymidylate synthase (TS), etc. While the effects of AUY922 50 mg/kgw are less statistically significant. Up to date, 5-fluorouracil (5-FU) or oral fluoropyrimidines are the current mainstay agents for first-line treatment in gastric cancer. By combining AUY922 100 mg/kgw i.p. and 5-fluorouracil (5-FU) 40 mg/kgw i.p. weekly (wk), tumor inhibitory effects of AUY922 and 5-FU were synergistically effective. Combining AUY922 50 mg/kgw or 100 mg/kgw i.p. weekly and other relevant chemotherapeutic agents has been also actively exploring. Our data indicate that AUY922 plus 5-fluorouracil (5-FU) inhibits tumors synergistically in gastric cancer MKN45 xenograft via down regulation of multiple pivotal growth factor receptors and oncoproteins. Since phase I study of AUY922 has been completed with favorable toxicity profiles, it is highly reasonable to combine AUY922 with 5-FU or other relevant chemotherapeutic agents in future development of clinical trials for gastric cancers. 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 2767. doi:1538-7445.AM2012-2767