title: The combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation in pancreatic cancer.
abstract: OBJECTIVE
  Gemcitabine-radiotherapy is a standard treatment for locally advanced pancreatic cancer. Clinical data have shown that gemcitabine plus erlotinib is superior to gemcitabine alone for advanced pancreatic cancer. Therefore, we investigated the effects of the combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation on a pancreatic cancer model.
  
  
  METHODS
  EGFR signaling was analyzed by measuring phosphorylated EGFR (pEGFR(Y845, (Y1173)) and AKT (pAKT(S473)) protein levels in pancreatic cancer cell lines and tumors. The effects of scheduling on gemcitabine-mediated cytotoxicity and radiosensitization combined with erlotinib were determined by clonogenic survival. In vivo, the effects of cetuximab or erlotinib in combination with gemcitabine-radiation on the growth of BxPC-3 tumor xenografts were measured.
  
  
  RESULTS
  We found in vitro that gemcitabine induced phosphorylation of EGFR at Y845 and Y1173 that was blocked by erlotinib. Treatment of BxPC-3 cells with gemcitabine before erlotinib enhanced gemcitabine-mediated cytotoxicity without abrogating radiosensitization. In vivo, cetuximab or erlotinib in combination with gemcitabine-radiation inhibited growth compared with gemcitabine-radiation (time to tumor doubling: gemcitabine + radiation, 19 +/- 3 days; cetuximab + gemcitabine + radiation, 30 +/- 3 days; P < 0.05, erlotinib + gemcitabine + radiation 28 +/- 3 days; P < 0.1). Cetuximab or erlotinib in combination with gemcitabine-radiation resulted in significant inhibition of pEGFR(Y1173) and pAKT(S473) early in treatment, and pEGFR(Y845), pEGFR(Y1173), and pAKT(S473) by the end of treatment. This study shows a novel difference pEGFR(Y845) and pEGFR(Y1173) in response to EGFR inhibition.
  
  
  CONCLUSIONS
  These results show that the EGFR inhibitors cetuximab and erlotinib increase the efficacy of gemcitabine-radiation. This work supports the integration of EGFR inhibitors with gemcitabine-radiation in clinical trials for pancreatic cancer.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109-5637, USA. mmccrack@med.umich.edu
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Morgan
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Parsels
authors.forename: Laura E
authors.initials: LE
authors.lastname: Kollar
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Normolle
authors.forename: Jonathan
authors.initials: J
authors.lastname: Maybaum
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
mesh_terms: D000230:Adenocarcinoma / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000628:therapy*; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D011878:Radiotherapy; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000068818:Cetuximab; D000093542:Gemcitabine