Abstract
PI3K-Akt is overexpressed in 50% to 70% of pancreatic ductal adenocarcinoma (PDAC). The hypothesis of this study is that PI3K and EGFR coinhibition may be effective in PDAC with upregulated PI3K-Akt signaling. Multiple inhibitors were tested on five PDAC cell lines. EGFR inhibitor (EGFRi)-resistant cell lines were found to have significantly overexpressed AKT2 gene, total Akt, and pAkt. In vitro erlotinib-resistant (ER) cell models (BxPC-ER and PANC-ER) with highly constitutively active PI3K-Akt were developed. These and their respective parent cell lines were tested for sensitivity to erlotinib, IGFIR inhibitor NVP-AEW541 (AEW), and PI3K-alpha inhibitor NVP-BYL719 (BYL), alone or in combination, by RTK-phosphoarray, Western blotting, immunofluorescence, qRT-PCR, cell proliferation, cell cycle, clonogenic, apoptosis, and migration assays. Erlotinib plus BYL was tested in vivo. Erlotinib acted synergistically with BYL in BxPC-ER (synergy index, SI = 1.71) and PANC-ER (SI = 1.44). Treatment of ER cell lines showing upregulated PI3K-Akt with erlotinib plus BYL caused significant G1 cell-cycle arrest (71%, P < 0.001; 58%, P = 0.003), inhibition of colony formation (69% and 72%, both P < 0.001), and necrosis and apoptosis (75% and 53%, both P < 0.001), more so compared with parent cell lines. In primary patient-derived tumor subrenal capsule (n = 90) and subcutaneous (n = 22) xenografts, erlotinib plus BYL significantly reduced tumor volume (P = 0.005). Strong pEGFR and pAkt immunostaining (2+/3+) was correlated with high and low responses, respectively, to both erlotinib and erlotinib plus BYL. PDAC with increased expression of the PI3K-Akt pathway was susceptible to PI3K-EGFR coinhibition, suggesting oncogenic dependence. Erlotinib plus BYL should be considered for a clinical study in PDAC; further evaluation of pEGFR and pAkt expression as potential positive and negative predictive biomarkers is warranted.
Highlights
Pancreatic ductal adenocarcinoma, pancreatic ductal adenocarcinoma (PDAC), has very poor prognosis, with 85% of patients presenting with locally advanced or metastatic disease [1]
Treatment of ER cell lines showing upregulated PI3K–Akt with erlotinib plus BYL caused significant G1 cell-cycle arrest (71%, P < 0.001; 58%, P 1⁄4 0.003), inhibition of colony formation (69% and 72%, both P < 0.001), and necrosis and apoptosis (75% and 53%, both P < 0.001), more so compared with parent cell lines
PDAC with increased expression of the PI3K–Akt pathway was susceptible to PI3K–EGFR coinhibition, suggesting oncogenic dependence
Summary
Pancreatic ductal adenocarcinoma, PDAC, has very poor prognosis, with 85% of patients presenting with locally advanced or metastatic disease [1]. Gemcitabine has been the cornerstone chemotherapy for advanced PDAC [2]. Authors' Affiliations: 1Cancer Surgery; 2Flow Cytometry Unit, Haematology Division; 3Hormones and Cancer Division, Kolling Institute of Medical Research, University of Sydney; Departments of 4Medical Oncology, 5Upper Gastrointestinal Surgery, and 6Pathology, Royal North Shore Hospital, Sydney, Australia. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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