Wong, matthew H, Xue, Aiqun, Julovi, Sohel M, Pavlakis, Nick, Samra, Jas S, Hugh, Thomas J, Gill, Anthony J, Peters, Lyndsay, Baxter, Robert C and Smith, Ross C (2014) NVP-BYL719, a novel PI3K-alpha selective inhibitor, overcomes acquired erlotinib resistance via upregulation of the PI3K/Akt/ mTOR pathway in pancreatic ductal adenocarcinoma. Clinical Cancer Research.

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with few treatment options. Epidermal growth factor receptor (EGFR) inhibitor erlotinib combined with gemcitabine only marginally improves survival, possibly due to development of acquired erlotinib resistance. In this study, we explore mechanisms of erlotinib resistance and propose PI3K and EGFR co-inhibition strategy to overcome this.
Methods: We developed in-vitro erlotinib resistant pancreatic cancer cell models by subculturing two cell lines (BxPC-3, PANC-1) in dose-esclating erlotinib for 9 months, and tested erlotinib, IGF1R inhibitor NVP-AEW541 and PI3K-alpha inhibitor NVP-BYL719, alone or in combination. Cell proliferation, RTK-phosphorarray, western blotting, confocal microscopy, cell cycle, apoptotic, clonogenic and migration assays were performed. We investigated the anti-tumour effect of erlotinib plus NVP-BYL719 in a primary patient-derived tumour xenograft mice model.
Results: Both acquired resistant cell lines showed activation of PI3K/Akt pathwy. They were cross-resistant to NVP-AEW541 and MEK inhibitor, but remained sensitive to NVP-BYL719. Importantly, erlotinib was synergistic with NVP-BYL719 in BxPC-ER (synergy index or S.I.=1.71) and PANC-ER (S.I.=1.44), more so than the respective parent cell lines. Treatment of resistant cell lines with erlotinib plus NVP-BYL719 caused substantial G1 cell cycle arrest (71% and 58%, respectively), inhibition of colony formation (69% and 72%), and considerable necrosis and apoptosis (65% and 53%), of greater magnitude than those observed in BxPC-3 and PANC-1. In-vivo, erlotinib plus NVP-BYL719 significantly reduced tumor volume by 11.20 mm3 (95% CI: 4.30-13.15mm3, P=0.012) compared to control.
Conclusion: Erlotinib-resistant PDAC cells appeared to become dependent on the PI3K/Akt pathway through oncogenic addiction, making them highly susceptible to PI3K/ EGFR co-inhibition. The pre-clinical efficacy of erlotinib plus NVP-BYL719 combination was established. Erlotinib plus NVP-BYL719 may have therapeutic relevance in pancreatic cancer, especially in erlotinib-refractory disease or those with activated PI3K pathway.

Item Type:	Article
Date Deposited:	18 May 2016 23:45
Last Modified:	18 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/9581