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Updated: Apr 5, 2026
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Published on: October 5, 2020
Epidermal Growth Factor Receptor Signaling to the Mitogen Activated Protein Kinase Pathway Bypasses Ras in Pancreatic
Sangjun Lee1, Eileen L Heinrich, Jianming Lu
1From the *Division of Surgical Oncology, Departments of Surgery and †Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA; and ‡Department of Surgery, Stony Brook Medicine, Stony Brook, NY.
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.
Insights
Epidermal growth factor receptor (EGFR) signaling in pancreatic cancer with K-ras mutations bypasses standard pathways. This suggests alternative routes to the MAPK pathway, impacting treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- Epidermal growth factor receptor (EGFR/HER1) is overexpressed in pancreatic cancers.
- Anti-EGFR therapy shows limited efficacy in pancreatic cancers with oncogenic K-ras mutations.
Purpose of the Study:
- To investigate the signaling relationship between EGFR and mutant K-ras in pancreatic cancer.
- To understand why anti-EGFR therapies are ineffective in K-ras mutated pancreatic cancers.
Main Methods:
- Pancreatic cancer cells with K-ras mutations were treated with EGF to analyze EGFR to MAPK pathway signaling.
- Short interfering RNA was used to assess the role of Ras proteins in transducing EGFR signals.
- Components of MAPK and PI3K pathways were examined for their involvement in EGFR signaling.
Main Results:
- EGF signaling in these cells selectively occurs through HER1.
- Knockdown of Ras isoforms did not inhibit EGF-mediated ERK phosphorylation.
- MEK inhibition completely blocked EGF-mediated ERK phosphorylation, while Raf inhibition partially reduced it.
- Inhibition of PI3K/AKT and CDC42/PAK pathways did not affect EGFR signaling.
Conclusions:
- EGFR-mediated signaling in K-ras mutant pancreatic cancer cells deviates from the canonical MAPK pathway.
- Novel, alternative signaling pathways to downstream MAPK exist in the presence of mutant K-ras, explaining therapeutic resistance.
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