Simultaneous targeting of 5-LOX-COX and EGFR blocks progression of pancreatic ductal adenocarcinoma

Abstract

// Chinthalapally V. Rao 1 , Naveena B. Janakiram 1 , Venkateshwar Madka 1 , Vishal Devarkonda 1 , Misty Brewer 1 , Laura Biddick 1 , Stan Lightfoot 1 , Vernon E. Steele 2 , Altaf Mohammed 1 1 Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA 2 Division of Cancer Prevention, Chemopreventive Agent Development Research Group, National Cancer Institute, Bethesda, MD, USA Correspondence to: Chinthalapally V. Rao, e-mail: cv-rao@ouhsc.edu Altaf Mohammed, e-mail: altaf-mohammed@ouhsc.edu Keywords: chemoprevention, inflammation, EGFR, pancreatic cancer Received: July 31, 2015      Accepted: September 16, 2015      Published: September 28, 2015 ABSTRACT Cyclooxygenase-2 (COX-2), 5-Lipoxygenase (5-LOX), and epidermal growth factor receptor (EGRF) are over-expressed in human pancreatic ductal adenocarcinoma (PDAC). Using next-generation sequencing (NGS) analysis, we show significant increase in COX-2, 5-LOX, and EGFR expression during PDAC progression. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and tumor resistance. To target COX-2, 5-LOX, and EGFR simultaneously, we tested effects of licofelone (dual 5-LOX-COX inhibitor), and gefitinib (EGFR inhibitor), individually and in combination, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC using genetically engineered mice. Individually, licofelone (L) and gefitinib (G) significantly inhibited incidence of PDAC in male (72% L, 90% G, p < 0.0001) and female (90% L, 85% G, p < 0.0001) mice. The combination drug treatment produced complete inhibition of PDAC in both genders. Pancreata of mice receiving combination treatment showed significantly fewer Dclk1-positive cancer stem-like cells, inhibition of COX-2, 5-LOX, PCNA, EGFR and β-catenin expression ( p < 0.05–0.0002), increased p21 expression. Significant changes in tumor immune responses and desmoplastic reaction was observed by NGS analysis in combination treatment ( p < 0.05). In summary, early simultaneous targeting of 5-LOX-COX- and EGFR pathways may provide additive inhibitory effects leading to complete suppression of PDAC.