Heat shock protein 90 (Hsp90) has been identified to be crucial for stability and functionality of oncogenic signaling molecules, including EGFR and various transcription factors. We recently demonstrated that pancreatic cancer harbors multiple such targets, which can effectively be inhibited by geldanamycin derivates, thus leading to significant growth inhibition in vivo. We now focused on the effects of Hsp90 inhibition on macrophage stimulating receptor-1 (MSR1) (also termed RON receptor) signaling in pancreatic cancer. This oncogenic receptor system has recently been implicated in pancreatic cancer progression, suggesting that MSR1 could be an interesting novel target for therapy.However, selective inhibitors to MSR1 are still under development, hence we hypothesized that Hsp90 inhibitors could also affect MSR1 signaling in pancreatic cancer cells. Human pancreatic cancer cells (L3.6pl, HPAF-II, Panc89, BxPc3, CAPAN-1) were investigated in experiments. For inhibiting Hsp90, the geldanamycin derivate 17DMAG and a novel synthetic inhibitor, EC154 (Biogen Idec), were used. Effects of Hsp90 blockade on macrophage stimulating protein-1 (MSP-1) induced signaling pathways in pancreatic cancer cells were investigated by Western blotting. The impact on MSP-1 mediated cell migration was evaluated in modified Boyden chambers. Effects of EC154 on MSR1 expression, tumor growth and vascularization, were investigated in subcutaneous and orthotopic xenograft models. The results showed that MSR1 is expressed by pancreatic cancer cells and MSP-1 activated Akt and Erk signaling intermediates. Moreover, MSP-1 induced cell migration in vitro. Both, MSP-1 signaling and migratory properties were substantially disrupted by Hsp90 inhibition. Importantly, blocking Hsp90 markedly down-regulated MSR1 expression in HPAF-II and Panc89 cancer cells. By sequencing, common polymorphisms were detectable in these particular cell lines, which did not correlate with down-regulation of MSR1, suggesting that other mechanisms may render MSR1 expression susceptible to Hsp90 inhibitors. In vivo, treatment with the Hsp90 inhibitor EC154 significantly reduced tumor growth rates of pancreatic cancer cells. Analyses of tumor tissues showed that blocking Hsp90 effectively diminished MSR-1 expression in L3.6pl pancreatic cancer tumors, suggesting that MSR1 is indeed a novel client protein of Hsp90 that can be targeted in vivo. Targeting Hsp90 is suitable for impairing MSR1 function in pancreatic cancer through down-regulation of MSR-1 and inhibition of its down-stream signaling. MSR1 appears to be a novel client protein of Hsp90.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2835.

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

American Association for Cancer Research
2009