title: Dual ErbB1 and ErbB2 receptor tyrosine kinase inhibition exerts synergistic             effect with conventional chemotherapy in pancreatic cancer.
abstract: Patient survival in pancreatic cancer remains poor with gemcitabine (GEM)-based             regimens. The target specific molecular agent lapatinib, a dual ErbB1 and ErbB2             receptor tyrosine kinase inhibitor, has shown significant activity against ErbB1             and ErbB2-expressing tumors. Since pancreatic tumors frequently overexpress these             proteins, we investigated its effects, both alone and in conjunction with 5-FU             or GEM. The pancreatic cancer cell lines PANC-1 and AsPC were treated with varying             doses of lapatinib in vitro. The effects on ErbB1/ErbB2 protein phosphorylation             and on the cell survival protein survivin were determined by western blotting.             Cytotoxicity was determined by MTT assay and apoptosis was measured using the             caspase-3 colorimetric assay. Similar dose-response lapatinib experiments were             conducted with varying concentrations of 5-FU or GEM and isobolograms were constructed             to evaluate therapeutic synergy. Lapatinib inhibited protein phosphorylation in             the range of 4-16 µM, a clinically achievable concentration. The lapatinib-treated             cells showed a dose-dependent inhibition of cell proliferation and induction of             apoptosis at the same concentrations that blocked ErbB1/ErbB2 phosphorylation.             The addition of 5-FU or GEM to these cells resulted in synergistic effects. The             lapatinib-treated cells also demonstrated downregulation of survivin. Simultaneous             dual ErbB1 and ErbB2 receptor tyrosine kinase inhibition with lapatinib results             in significant reduction of pancreatic cancer cell growth and proliferation. These             effects occur at clinically achievable concentrations and are synergistic with             the effects of 5-FU or GEM. These findings support the potential role of lapatinib             in the treatment of pancreatic cancer.
authors.affiliation: Department of Surgery, Temple University Hospital, Philadelphia, PA 19104, USA. smit.singla@tuhs.temple.edu
authors.forename: Smit
authors.initials: S
authors.lastname: Singla
authors.forename: James A
authors.initials: JA
authors.lastname: Pippin
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Drebin
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D000077341:Lapatinib; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D066246:ErbB Receptors; D005472:Fluorouracil; D051034:Inhibitor of Apoptosis Proteins; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077022:Survivin; D000093542:Gemcitabine; C107489:BIRC5 protein, human; C508053:ERBB2 protein, human