Details

Autor(en) / Beteiligte

• Lee, Sangjun
• Heinrich, Eileen L
• Lu, Jianming
• Lee, Wendy
• Choi, Audrey H
• Luu, Carrie
• Chung, Vincent
• Fakih, Marwan
• Kim, Joseph

Titel

Epidermal Growth Factor Receptor Signaling to the Mitogen Activated Protein Kinase Pathway Bypasses Ras in Pancreatic Cancer Cells

Ist Teil von

• Pancreas, 2016-02, Vol.45 (2), p.286-292

Ort / Verlag

United States

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. 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.