Heat shock protein 90 (Hsp90) is a conserved molecular chaperone mediating the maturation and stability of several cancer-associated proteins. Hsp90 is an emerging target in cancer, and high Hsp90 expression has been linked to decreased survival in breast cancer. IPI-504 is a novel inhibitor of Hsp90 which is currently in clinical trials in gastrointestinal stromal tumors (GIST, Phase III) and NSCLC (Phase II). The aim of this study was to assess the anti-tumor effects of IPI-504 in trastuzumab resistant, HER2 positive breast cancer cells. We developed HER2 positive breast cancer cell lines (BT-474 and SKBR-3) resistant to trastuzumab by culturing cells in the presence of increasing concentrations of trastuzumab for more than 18 months. These cells are refractory to the antiproliferative activity of trastuzumab at doses up to 250nM in the culture medium. IPI-504 inhibits the growth of parental (BT-474 and SKBR3) as well as trastuzumab resistant cell lines. By western blot analysis we show that IPI-504 is equally efficient in decreasing the levels of HER2, Akt, p-Akt and p-MAPKs in both parental and resistant cells. Similarly, inhibition of proliferation with accumulation in G0-G1 phase of the cell cycle in both cell types is achieved by comparable concentrations of IPI-504. In vivo, the growth of xenografts derived from parental BT-474 cells was, as expected, inhibited by both trastuzumab and IPI-504. In contrast, xenografts derived from trastuzumab resistant BT-474 cells responded poorly to trastuzumab but were still sensitive to IPI-504. Interestingly, the combination of trastuzumab and IPI-504 was found to be more effective than either agent alone in trastuzumab resistant tumors. In trastuzumab sensitive tumors, HER2 downregulation was effectively achieved with either trastuzumab or IPI-504, whereas in trastuzumab resistant tumors only the combination of both compounds significantly decreased the levels of HER2. In a time course experiment using trastuzumab resistant xenografts we found that the levels of HER2, p-Akt and p-MAPK were significantly decreased after 12 hours of a single dose of IPI-504, reaching minimum levels at 24 hours. At 48 hours, both p-Akt and p-MAPK recovered, whereas HER2 levels were still low. Taken together, these results suggest that the inhibition of Hsp90 by IPI-504 can represent a valid therapeutic option in trastuzumab resistant breast cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4712.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009