title: Erlotinib prolongs survival in pancreatic cancer by blocking gemcitabine-induced MAPK signals.
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.
authors: Department of Gastroetnterology, Graduate School of Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Koji
authors: K
authors: Miyabayashi
authors: Hideaki
authors: H
authors: Ijichi
authors: Dai
authors: D
authors: Mohri
authors: Motohisa
authors: M
authors: Tada
authors: Keisuke
authors: K
authors: Yamamoto
authors: Yoshinari
authors: Y
authors: Asaoka
authors: Tsuneo
authors: T
authors: Ikenoue
authors: Keisuke
authors: K
authors: Tateishi
authors: Yousuke
authors: Y
authors: Nakai
authors: Hiroyuki
authors: H
authors: Isayama
authors: Yasuyuki
authors: Y
authors: Morishita
authors: Masao
authors: M
authors: Omata
authors: Harold L
authors: HL
authors: Moses
authors: Kazuhiko
authors: K
authors: Koike
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004797:Enzyme-Linked Immunosorbent Assay; D000069347:Erlotinib Hydrochloride; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D011799:Quinazolines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D011799:Quinazolines; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine