RRC ID 44286
Author Miyabayashi K, Ijichi H, Mohri D, Tada M, Yamamoto K, Asaoka Y, Ikenoue T, Tateishi K, Nakai Y, Isayama H, Morishita Y, Omata M, Moses HL, Koike K.
Title Erlotinib prolongs survival in pancreatic cancer by blocking gemcitabine-induced MAPK signals.
Journal Cancer Res.
Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers worldwide. Although many regimens have been used for PDAC treatment, the combination of the EGF receptor (EGFR) inhibitor erlotinib with gemcitabine has been the only molecular-targeted drug tested so far that has been superior to gemcitabine alone. The mechanism underlying this effective combinational regimen remains unknown. Here, we show that the combination is superior to gemcitabine alone in blocking progression and prolonging survival in a murine model of PDAC (Kras activation with Tgfbr2 knockout). We found that gemcitabine induced mitogen-activated protein kinase signaling, which was dramatically inhibited by erlotinib even in the Kras-activated PDAC cells in the mouse model. Mechanistic investigations suggested that gemcitabine induces EGFR ligand expression and ERBB2 activation by increasing heterodimer formation with EGFR, thereby maintaining high levels of ERBB2 protein in PDAC cells. Overall, our findings suggest a significant role of ERBB in PDAC treatment.
Volume 73(7)
Pages 2221-34
Published 2013-4-1
DOI 10.1158/0008-5472.CAN-12-1453
PII 0008-5472.CAN-12-1453
PMID 23378339
MeSH Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology* Apoptosis / drug effects* Blotting, Western Carcinoma, Pancreatic Ductal / drug therapy Carcinoma, Pancreatic Ductal / metabolism Carcinoma, Pancreatic Ductal / mortality* Cell Proliferation / drug effects Deoxycytidine / administration & dosage Deoxycytidine / analogs & derivatives Enzyme-Linked Immunosorbent Assay Erlotinib Hydrochloride Flow Cytometry Immunoenzyme Techniques Immunoprecipitation Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinases / genetics Mitogen-Activated Protein Kinases / metabolism* Pancreatic Neoplasms / drug therapy Pancreatic Neoplasms / metabolism Pancreatic Neoplasms / mortality* Phosphorylation / drug effects Protein-Serine-Threonine Kinases / physiology* Proto-Oncogene Proteins p21(ras) / physiology* Quinazolines / administration & dosage RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta / physiology* Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Survival Rate Tumor Cells, Cultured
IF 9.13
Times Cited 15
Human and Animal Cells