Blockade of the epidermal growth factor receptor (EGFR) by EGFR tyrosine kinase inhibitors is insufficient for effective anti-tumor activity because the reactivation of the ErbB3 signaling pathway significantly contributes to activating the consequent phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Combinatorial therapies including ErbB3 targeting may ameliorate tumor responses to anti-EGFR therapies. In the present study, we found that in BxPC-3 and L3.6pl cells, which highly expressed the ErbB3 receptor, significant reduction in cell viability, induction of apoptosis were observed when treated with a combination of erlotinib and PF compared to either agent alone. Moreover, in ErbB3-expressing BxPC-3, L3.6pl and S2VP10 cell lines, the inhibition of ErbB3/PI3K/Akt phosphorylation were observed when treated with PF. Most strikingly, both EGFR/MAPK/Erk and ErbB3/PI3K/Akt activitions were substantially suppressed when treated with the combination of PF and erlotinib. However, in the ErbB3-deficient cell line MIAPaCa-2, no such effects were observed with similar treatments. Most importantly, these in vitro results were replicated in nude mouse transplanted tumor models. Taken together, our findings show that PF enhances the effect of erlotinib in ErbB3-expressing pancreatic cancer cells by directly suppressing ErbB3 activation, and PF in combination with erlotinib is much more effective as an antitumor agent compared with either agent alone.