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Mesothelin and TGF-α predict pancreatic cancer cell sensitivity to EGFR inhibitors and effective combination treatment with trametinib.
Poteet, Ethan; Liu, Dongliang; Liang, Zhengdong; Van Buren, George; Chen, Changyi; Yao, Qizhi.
Afiliação
  • Poteet E; Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, Texas, United States of America.
  • Liu D; Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, Texas, United States of America.
  • Liang Z; Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, Texas, United States of America.
  • Van Buren G; Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, Texas, United States of America.
  • Chen C; Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, Texas, United States of America.
  • Yao Q; Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS One ; 14(3): e0213294, 2019.
Article em En | MEDLINE | ID: mdl-30921351
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Protocolos de Quimioterapia Combinada Antineoplásica / Fator de Crescimento Transformador alfa / Resistencia a Medicamentos Antineoplásicos / Carcinoma Ductal Pancreático / Proteínas Ligadas por GPI Tipo de estudo: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Protocolos de Quimioterapia Combinada Antineoplásica / Fator de Crescimento Transformador alfa / Resistencia a Medicamentos Antineoplásicos / Carcinoma Ductal Pancreático / Proteínas Ligadas por GPI Tipo de estudo: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article