Abstract 590: Antiproliferative effects and signaling profiles of the novel HSP90 inhibitor NVP-AUY922 in non-small cell lung cancer

Background; Gefitinib and erlotinib, which have been designed to inhibit tyrosine kinase of epidermal growth factor receptor (EGFR), showed drastic anti-tumor effect on NSCLCs with common EGFR mutations, but acquired resistance is a major problem to failure this treatment. Heat shock protein (HSP) 90 inhibitors have been developed as promising anti-cancer agents, because HSP90, a molecular chaperone, plays a pivotal role in NSCLC survival as it stabilizes a large set of client proteins, many of which are important for tumor cell survival and proliferation. In this study, we examined “NVP-AUY922,” a new HSP90 inhibitor, and showed its effects against NSCLCs. Methods: We used 24 NSCLC cell lines with specific genetic alterations, which are K-ras mutation, B-raf mutation and EGFR mutation. Cell proliferation was determined by modified MTS assay. The expressions of client proteins were assessed by Western Blotting. Results: NVP-AUY922 exhibited strong antiproliferative effects to most NSCLC cell lines, except H1395 and Calu3. One of resistant cells is a B-raf mutator and another has no specific genetic alterations, but NSCLCs with EGFR mutations were sensitive. The average IC50 of NVP-AUY922 in sensitive cells was 18.7 + 8.32 nM. In most cell lines, higher depletion of both total and phosphorylated client proteins such as MET, HER2, EGFR and AKT, were shown by NVP-AUY922 treatment with higher concentration. But in Calu3, a resistant cell line, they did not decrease in lower concentration. MET, HER2 and EGFR were suppressed for whole duration tested, while the expression of AKT was depleted for 48 hours and then recovered at 72 hours after treatment. The client protein of H1395 decreased in lower concentration and the cause of resistance to NVP-AUY922 has been unknown so far. Conclusions; NVP-AUY922 was effective to most NSCLC cell lines at low concentration and suggested to be a promising new drug of NSCLCs, even those resistant to EGFR-TKIs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 590. doi:10.1158/1538-7445.AM2011-590