Background: Pancreatic cancer epidermal growth factor receptor (EGFR) signaling contributes to tumorigenesis and EGFR-targeted agents (erlotinib) have been approved for pancreatic cancer treatment. EGFR protein expression however does not correlate with pancreatic cancer sensitivity to erlotinib and there is a need to identify surrogate markers of response and prognosis. ErbB3 is another ErbB-family tyrosine kinase receptor that interacts with EGFR via heterodimerization and that may influence cancer aggressiveness and patient survival. We sought to describe the prognostic significance of ErbB3 pathway signaling in pancreatic cancer patients while analyzing the relationship between ErbB3 expression and in vitro sensitivity to erlotinib.

Methods: Laser-capture microdissection was utilized to specifically extract RNA and protein from 31 pancreatic cancer surgical tumor specimens. Expression of ErbB3 transcript was measured with RT-PCR. Expression of ErbB3’s ligands neuregulin-α and -β (NRG), activated ErbB3 (pErbB3) and activated Akt (pAkt) was quantified with immunohistochemical staining scores and correlated to patient survival. In vitro, quantitative real-time PCR ErbB3 transcript levels were compared with sensitivity to erlotinib in 9 human pancreatic cancer cell lines. The effects of ErbB3 siRNA inhibition on pancreatic cancer cell response to erlotinib were also analyzed.

Results: All 31 pancreatic cancer patients displayed ErbB3 transcript, with 50% expressing p-ErbB3. pAkt expression showed no correlation with patient survival. NRG was present in 86% of tumors, with localization patterns reflecting both autocrine and paracrine supply. As expected, higher NRG protein expression levels were directly associated with ErbB3 activation as determined by p-ErbB3 expression (p=0.002). High (above-median) NRG-α expression was associated with longer median overall patient survival (24.7 vs. 13.7 months, p=0.032). In vitro, NRG-β stimulation induced robust proliferation in ErBB3-expressing pancreatic cancer cells. Elevated ErbB3 transcript levels correlated with inhibition of proliferation by erlotinib (p=0.027) and temporary knock-down of pancreatic cancer cell ErbB3 by RNA interference led to resistance to erlotinib.

Conclusions: Pancreatic cancer expression of the ErbB3 ligand NRG-β is associated with improved postoperative patient survival. ErbB3 expression in vitro determines pancreatic cancer cell sensitivity to erlotinib possibly through lateral interaction with EGFR. Analysis of ErbB3 pathway signaling including expression of its ligand NRG may serve as prognostic factors in pancreatic cancer patient selection for anti-EGFR therapy strategies.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA