Dual ErbB1 and ErbB2 receptor tyrosine kinase inhibition exerts synergistic effect with conventional chemotherapy in pancreatic cancer

Patient survival in pancreatic cancer remains poor with gemcitabine (GEM)-basedregimens. The target specific molecular agent lapatinib, a dual ErbB1 and ErbB2receptor tyrosine kinase inhibitor, has shown significant activity against ErbB1and ErbB2-expressing tumors. Since pancreatic tumors frequently overexpress theseproteins, we investigated its effects, both alone and in conjunction with 5-FUor GEM. The pancreatic cancer cell lines PANC-1 and AsPC were treated with varyingdoses of lapatinib in vitro. The effects on ErbB1/ErbB2 protein phosphorylationand on the cell survival protein survivin were determined by western blotting.Cytotoxicity was determined by MTT assay and apoptosis was measured using thecaspase-3 colorimetric assay. Similar dose-response lapatinib experiments wereconducted with varying concentrations of 5-FU or GEM and isobolograms were constructedto evaluate therapeutic synergy. Lapatinib inhibited protein phosphorylation inthe range of 4-16 µM, a clinically achievable concentration. The lapatinib-treatedcells showed a dose-dependent inhibition of cell proliferation and induction ofapoptosis at the same concentrations that blocked ErbB1/ErbB2 phosphorylation.The addition of 5-FU or GEM to these cells resulted in synergistic effects. Thelapatinib-treated cells also demonstrated downregulation of survivin. Simultaneousdual ErbB1 and ErbB2 receptor tyrosine kinase inhibition with lapatinib resultsin significant reduction of pancreatic cancer cell growth and proliferation. Theseeffects occur at clinically achievable concentrations and are synergistic withthe effects of 5-FU or GEM. These findings support the potential role of lapatinibin the treatment of pancreatic cancer.