Cotargeting of epidermal growth factor receptor and PI3K overcomes PI3K-AKT oncogenic dependence in pancreatic ductal adenocarcinoma

Matthew H. Wong, Aiqun Xue, Sohel M. Julovi, Nick Pavlakis, Jaswinder S. Samra, Thomas J. Hugh, Anthony J. Gill, Lyndsay Peters, Robert C. Baxter, Ross C. Smith*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: 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. Results: Erlotinib acted synergisticallywith 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%, bothP< 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)4047-4058
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number15
DOIs
Publication statusPublished - 1 Aug 2014
Externally publishedYes

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