Abstract #3697: Combination of Hsp90 inhibitors and MEK inhibitors abrogates ERK activation in pancreatic cancer cells

Purpose. The Ras/Raf/MEK/ERK signal transduction cascade is one of the most important MAPK pathway, which is deregulated and constitutively activated in pancreatic cancer. Hsp90 inhibitors lead to the degradation of Hsp90 client proteins, including many proteins involved in the ERK pathway. This study is to investigate the mechanism of transient activation of MEK/ERK signaling cascade by Hsp90 inhibitors and combination effects of Hsp90 inhibitors and MEK inhibitor in pancreatic cancer cells. Methods. Western blotting was used to determine the oncogenic protein levels after Hsp90 inhibition and MEK inhibition. MTS assay was performed to test the anti-proliferation effect after single and combined treatment. Apoptosis was monitored by caspase-3 activity. Results. Hsp90 inhibitor (17AAG) induced a transient increase (3 to 6-fold) of phospho-ERK1/2 in pancreatic cancer cell lines in a concentration-dependent manner (0.1-5 µM). The phosphorylated ERK1/2 peaked at 1 h and gradually decreased to basal or even non-detectable level within 6-8 hrs, depending on the concentration of 17AAG. At the peak time of ERK activation, the caspase-3 activity was lower than the control without 17AAG treatment. The selective MEK1/2 inhibitor (U0126) completely abolished the transient activation of phospho-ERK1/2 induced by 17AAG. Combination treatment with U0126 and 17AAG in five pancreatic cancer cell lines showed additive or synergistic effect on anti-proliferation and induction of apoptosis. Conclusion. The inhibition of ERK pathway potentiated the anti-tumor effect of Hsp90 inhibitors, which probably via the abrogation of the ERK transient activation by Hsp90 inhibition.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3697.