Erlotinib prolongs survival in pancreatic cancer by blocking gemcitabine-induced MAPK signals.

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
Cancer Res. 2013 73 (7): 2221-34

PMID: 23378339 · DOI:10.1158/0008-5472.CAN-12-1453

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.

©2013 AACR.

MeSH Terms (29)

Animals Antineoplastic Combined Chemotherapy Protocols Apoptosis Blotting, Western Carcinoma, Pancreatic Ductal Cell Proliferation Deoxycytidine Enzyme-Linked Immunosorbent Assay Erlotinib Hydrochloride Flow Cytometry Immunoenzyme Techniques Immunoprecipitation Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinases Pancreatic Neoplasms Phosphorylation Protein-Serine-Threonine Kinases Proto-Oncogene Proteins p21(ras) Quinazolines Real-Time Polymerase Chain Reaction Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Signal Transduction Survival Rate Tumor Cells, Cultured

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