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Pancreatic Cancer Erbb3 Pathway Activation Is Associated with Erlotinib Sensitivity in Vitro and Improved Postoperative Patient Survival
Ching-Wei D. Tzeng*1, Andrey Frolov1, Nirag Jhala2, Natalya Frolova2, John H. Harrison1, Selwyn M. Vickers4, Donald J. Buchsbaum3, Martin J. Heslin1, Juan P. Arnoletti1
1Surgery, Univ of AL at Birmingham, Birmingham, AL; 2Pathology, Univ of AL at Birmingham, Birmingham, AL; 3Radiation Oncology, Univ of AL at Birmingham, Birmingham, AL; 4Surgery, Univ of Minnesota, Minneapolis, MN

Introduction:Epidermal growth factor receptor (EGFR) is an ErbB tyrosine kinase (TK) receptor that has been implicated in pancreatic cancer tumorigenesis. Erlotinib is an EGFR-specific TK inhibitor recently approved for treatment of pancreatic cancer. ErbB3 is another ErbB-family receptor which interacts with EGFR signaling and is also expressed by the majority of pancreatic cancers. We sought to analyze the influence of ErbB3 expression on pancreatic cancer cell sensitivity to erlotinib and the relationship of ErbB3 pathway activation with pancreatic cancer patient survival.
Methods: ErbB3 transcript levels were measured in nine pancreatic cancer cell lines using real time PCR (RT-PCR). ErbB3 expression levels were correlated with the effects of erlotinib on cell proliferation in vitro. Surgically resected pancreatic adenocarcinoma specimens (n=31) were laser-capture microdissected, and EGFR and ErbB3 expression levels were measured by RT-PCR. Expression levels of neuregulin-β (NRG, an ErbB3 ligand) and phosphorylated-ErbB3 (p-ErbB3) proteins were measured by immunohistochemistry. Downstream adaptor protein activation was evaluated with immunoblot for p-Akt. Expression of ErbB3, NRG, p-ErbB3, and p-Akt, was correlated with pancreatic cancer patient survival using univariate and multivariate analyses.
Results: Higher ErbB3 transcript levels were directly correlated with greater anti-proliferative effects and improved pancreatic cancer cell sensitivity to erlotinib (p=0.027). Among the resected 31 pancreatic cancer specimens, 71% expressed EGFR, and 100% expressed ErbB3, with 50% and 65% displaying p-ErbB3 and p-Akt protein, respectively. ErbB-3 ligand (NRG) was present in 86% of tumors, with localization patterns suggesting both autocrine and paracrine supply. Intensity of NRG expression was strongly correlated with p-ErbB3 protein levels (p=0.002), providing direct evidence of ErbB3 pathway activation. Elevated NRG expression was the only parameter associated with improved postoperative pancreatic cancer patient survival (median 24.7 vs. 13.7 months, p=0.03). Accounting for age >60, tumor stage, and p-Akt expression, Cox regression confirmed this positive association between NRG and survival (p=0.042).
Conclusions: Increased levels of pancreatic cancer cell ErbB3 result in improved sensitivity to erlotinib in vitro. Higher pancreatic cancer NRG levels are associated with improved postoperative patient survival. NRG overexpression and ErbB3 pathway activation seem to influence pancreatic cancer clinical outcome and may serve as favorable prognostic factors when selecting patients for EGFR-targeted therapeutic strategies.

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