Date Published: March 28, 2019
Publisher: Public Library of Science
Author(s): Ethan Poteet, Dongliang Liu, Zhengdong Liang, George Van Buren, Changyi Chen, Qizhi Yao, Aamir Ahmad.
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.
The epidermal growth factor receptor (EGFR; ErbB-1) is a transmembrane tyrosine kinase receptor capable of regulating a diverse array of cellular functions including growth, survival, cell migration, and differentiation . Activation of EGFR and its downstream pathways is a significant event in the formation of pancreatic ductal adenocarcinoma (PDAC), reinforcing ERK pathway activation to promote tumor transformation after the initial driver mutation(s) occur in KRAS . Although the ERK pathway is a primary driver of PDAC, EGFR also signals through the STAT, Akt/PI3K, and PLC-γ pathways, and can directly translocate to the nucleus to activate c-myc and cyclin-D1 [3,4]. The utility of EGFR inhibition is disease dependent, with distinct pathways affected in different diseases. Identifying the specific pathways that are inhibited is critical for assessing the effectiveness of EGFR inhibition in PDAC.
The aim of this study was to understand how EGFR inhibitors affect PDAC cells, and to determine if predictive biomarkers from other cancers could be adapted to PDAC. Furthermore, because of uncertainty regarding the clinical effectiveness of combination gemcitabine and erlotinib, we considered the cellular mechanisms underlying EGFR inhibition in PDAC, and how they could be used to select a more potent drug combination.