Epidermal Growth Factor Receptor Signaling to the Mitogen Activated Protein Kinase Pathway Bypasses Ras in Pancreatic Cancer Cells. Issue 2 (February 2016)

• Record Type: Journal Article
• Authors: Lee, Sangjun; Heinrich, Eileen L.; Lu, Jianming; Lee, Wendy; Choi, Audrey H.; Luu, Carrie; Chung, Vincent; Fakih, Marwan; Kim, Joseph
• Is Part Of: Pancreas. Volume 45:Issue 2(2016)
• Publication Date: 2016-02
• Subjects: EGFR -- K-ras -- MAPK -- therapeutic resistance -- pancreatic cancer; Pancreas -- Diseases -- Periodicals; Pancreas -- Periodicals; Neuroendocrine tumors -- Periodicals; 616.37005
• DOI: 10.1097/MPA.0000000000000379
• Languages: English
• ISSNs: 0885-3177

Abstract

Abstract : Objective: Epidermal growth factor (EGF) receptor (EGFR/HER1) is overexpressed in human pancreatic cancers. However, anti-EGFR therapy does not exhibit significant therapeutic activity with oncogenic K- ras mutation. We sought to assess the signaling relationship between EGFR and mutant K- ras, which is commonly detected in pancreatic cancer. Methods: Pancreatic cancer cells harboring mutated K- ras were treated with EGF to assess signaling from EGFR to mitogen-activated protein kinase (MAPK) pathway. The role of Ras family of proteins in transducing EGFR signals was assessed using short interfering RNA. Other components of MAPK and PI3K (phosphoinositide 3-kinase) pathways were examined for their roles in EGFR signaling. Results: First, EGF signaling in pancreatic cancer cells occurs selectively through HER1. Second, knockdown of all Ras isoforms failed to block EGF-mediated phosphorylation of extracellular signal-regulated kinase (ERK). Inhibition of Raf was observed to partially abrogate ERK phosphorylation, whereas MEK inhibition resulted in complete attenuation of EGF-mediated ERK phosphorylation. Finally, inhibition of phosphoinositide 3-kinase/AKT and CDC42/PAK pathways did not block EGFR signaling. Conclusions: Our study results demonstrate that EGFR-mediated signaling in mutant K- ras pancreatic cancer cells does not follow canonical MAPK signaling. Our novel findings suggest the existence of alternate signaling pathways to downstream MAPK in the presence of mutant K- ras . Abstract : Supplemental digital content is available in the text.