Abstract #2753: Biologic effects of NVP-AUY922, a novel small molecule inhibitor of HSP90 in human colon and gastric cancer cell lines

Background: Heat Shock Protein 90 (HSP90) enables the activation of a large numberof client chaperone proteins that have been implicated in gastrointestinal oncogenesis, a process that also includes HER2 and the Mismatch Repair system. NVP-AUY 922 is a small molecule inhibitor that potently inhibits HSP90 (Kd = 1.7 nmol/L) and is currently in Phase I clinical trials. To explore its potential clinical utility in colon and gastric cancer, we sought to evaluate the effect of NVP-AUY922 in a panel of molecularly characterized human colon and gastric cancer cell lines. Methods: A panel of 27 human colon and 15 gastric adenocarcinoma cancer cell lines were exposed in vitro to NVP-AUY922 over 12 concentrations to generate dose response curves. The ability of NVP-AUY922 to inhibit proliferation and induce cell death was measured and IC₅₀ and LD₅₀ values were calculated. Baseline gene expression profiles of the cell lines were also generated using the Agilent microarray platform. Results: NVP-AUY922 was found to have potent anti-proliferative activity in the low nanomolar range (< 40 nM) in over two thirds (20/27) of the colon cancer cell lines. In addition, the majority of cell lines had LD₅₀ values less than 100 nM. Similarly, in the gastric cancer panel, 12/15 cell lines had IC₅₀ values less than 100 nm and the majority had LD₅₀ values less than 100 nM as well. Molecular profiling of the colon lines confirmed that cells representing microsatellite stable and microsatelite instable subtypes were represented and both were sensitive to the effects of NVP-AUY 922. Among the gastric cancer group, molecular profiling identified subtypes that were both HER2 and MET amplified. The two lines that displayed high HER2 amplification (N87, OE19) were among the most sensitive to the anti-proliferative effects of NVP-AUY922. Conclusions: These data suggest that NVP-AUY922 is a potent inhibtior of tumor cell growth and is active against colon and gastric cancer cells in vitro. Ongoing molecular analyses are aimed at identifying predictive markers for sensitivity and resistance using the baseline gene expression profiles. NVP-AUY922 may have broad anti-tumor effects based on these data and support its ongoing clinical develoment in gastrointestinal cancers. The relationship between HER2, c-MET and HSP90 in gastric cancer merits further exploration.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2753.