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

Chinthalapally V. Rao*, Naveena B. Janakiram, Venkateshwar Madka, Vishal Devarkonda, Misty Brewer, Laura Biddick, Stan Lightfoot, Vernon E. Steele, Altaf Mohammed

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish
Pages (from-to)33290-33305
Number of pages16
JournalOncotarget
Volume6
Issue number32
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Chemoprevention
  • EGFR
  • Inflammation
  • Pancreatic cancer

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