Targeting Hsp90 is an attractive strategy for anticancer
therapy because the diversity and relevance of biological processes are regulated by these
proteins in most
cancers. However, the role and mode of action of Hsp90 inhibitors in
pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor,
IPI-504, in
pancreatic cancer and to determine the
biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by
IPI-504 exerts antiproliferative effects in a panel of
pancreatic cancer cells in a dose- and time-dependent manner. In
pancreatic cancer xenografts obtained directly from patients with
pancreas cancer, the agent resulted in a marked suppression of
tumor growth. Although known Hsp90 client
proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these
proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted
tumors. Using a proteomic profiling analysis with
isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated
proteins and 42 up-regulated
proteins on
IPI-504 treatment.
tumor growth Identical changes were observed in the expression of the genes coding for these
proteins in a subset of
proteins including HSPA1B,
LGALS3, CALM1, FAM84B, FDPS, GOLPH2,
HBA1, HIST1H1C,
HLA-B, and MARCKS. The majority of these
proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that
IPI-504 has potent antitumor activity in
pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling.