Mesothelin and TGF-α predict pancreatic cancer cell sensitivity to EGFR inhibitors and effective combination treatment with trametinib

PLoS One. 2019 Mar 28;14(3):e0213294. doi: 10.1371/journal.pone.0213294. eCollection 2019.

Abstract

Clinical trials of EGFR inhibitors in combination with gemcitabine for the treatment of pancreatic ductal adenocarcinoma (PDAC) have generated mixed results partially due to the poorly defined effectiveness of EGFR inhibitors in PDAC. Here, we studied a panel of PDAC cell lines to compare the IC50s of the EGFR inhibitors gefitinib and cetuximab. We found that gefitinib induced biphasic inhibition in over 50% of PDAC cells, with the initial growth inhibition occurring at nanomolar concentrations and a second growth inhibition occurring outside the clinical range. In contrast to gefitinib, cetuximab produced a single phase growth inhibition in a subset of PDAC cells. Using this sensitivity data, we screened for correlations between cell morphology proteins and EGFR ligands to EGFR inhibitor sensitivity, and found that mesothelin and the EGFR ligand TGF-α have a strong correlation to gefitinib and cetuximab sensitivity. Analysis of downstream signaling pathways indicated that plc-γ1 and c-myc were consistently inhibited by EGFR inhibitor treatment in sensitive cell lines. While an inconsistent additive effect was observed with either cetuximab or gefitinib in combination with gemcitabine, the cell pathway data indicated consistent ERK activation, leading us to pursue EGFR inhibitors in combination with trametinib, a MEK1/2 inhibitor. Both cetuximab and gefitinib in combination with trametinib produced an additive effect in all EGFR sensitive cell lines. Our results indicate that mesothelin and TGF-α can predict PDAC sensitivity to EGFR inhibitors and a combination of EGFR inhibitors with trametinib could be a novel effective treatment for PDAC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Cycle
  • Cell Proliferation
  • Cetuximab / administration & dosage
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / antagonists & inhibitors
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism*
  • Gefitinib / administration & dosage
  • Humans
  • Mesothelin
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Pyridones / administration & dosage
  • Pyrimidinones / administration & dosage
  • Signal Transduction
  • Transforming Growth Factor alpha / genetics
  • Transforming Growth Factor alpha / metabolism*
  • Tumor Cells, Cultured

Substances

  • GPI-Linked Proteins
  • Pyridones
  • Pyrimidinones
  • TGFA protein, human
  • Transforming Growth Factor alpha
  • trametinib
  • EGFR protein, human
  • ErbB Receptors
  • Mesothelin
  • Cetuximab
  • Gefitinib