Rationale: Pancreatic cancer (PC) is associated with advanced presentation and poor survival. Currently approved therapies, including EGFR inhibitors, have minimal effect on patient survival. PCs have a high incidence of activated Ras, which may bypass inhibition of EGFR, resulting in resistance to EGFR inhibitors. HSP90 is a ubiquitous molecular chaperone that specifically enables numerous protein kinases involving cell survival, including EGFR and MAPK pathway. Therefore, we hypothesized that simultaneous or sequential inhibition of EGFR and HSP90 would give a synergistic effect on cell viability in pancreatic cancer cell lines. Methods: We used two pancreatic cancer cell lines PANC1 and MiaPaCa2, both of which have activating K-ras mutations. EGFR inhibitor, compund 56 (cmp56), HSP90 inhibitor geldanamycin were used. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by PARP cleavage. The effect of EGFR and HSP 90 inhibition on relevant cell signaling pathways was assessed by immunoblotting with activation-specific phosphoantibodies directed against MAP kinases. Results: Growth inhibition was significantly (P < 0.05) higher in MiaPaCa2 cells treated with cmp56 and geldanamycin (62%) than cells treated with either cmp56 (13%) or geldanamycin (40%) or sequentially(cmp56 followed by geldanamycin, 28%). In Panc1 cells, growth inhibition was significantly (P < 0.05) higher, when treated with cmp56 and geldanamycin (40%) than cells treated with either cmp56 (10%) or geldanamycin (26%) or sequentially (33%). Concomitant Inhibition of EGFR and HSP90 was associated with decrease in phosphorylation of JNK and increase in PARP cleavage in MiaPaCa2 cells. Conclusions:These results suggest that combined inhibition of EGFR and HSP 90 could be a potential stategy in developing targeted therapeies in pancreatic cancer. Our findings also suggest that cmp56, an EGFR inhibitor, might play an important role in regulating the apoptotic response to geladanamycin and that multi-site targeting of growth signaling and cell survival pathways could provide a potent and novel strategy to treat patients with pancreatic cancer. We are studying further to undestand the molecualr pathways involved in this strategy.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4674.

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