title: Preclinical rationale for combining an EGFR antibody with cisplatin/gemcitabine for the treatment of NSCLC.
abstract: BACKGROUND
  Although the addition of epidermal growth factor receptor (EGFR) antibodies to various platinum-based chemotherapy regimens for non-small cell lung cancer (NSCLC) is being actively pursued in the clinic, rationale for the prioritization of specific regimens is lacking.
  
  
  METHODS
  We evaluated the antitumor effects of necitumumab, a recombinant human IgG1 antibody targeting EGFR, in combination with cisplatin plus gemcitabine, pemetrexed, or paclitaxel in a panel of 9 subcutaneous tumor models of NSCLC established in nu/nu athymic mice.
  
  
  RESULTS
  Necitumumab in combination with cisplatin/gemcitabine was particularly effective, although interestingly, the mechanisms underlying these benefits were model dependent. For example, increased tumor cell apoptosis contributed towards combination efficacy in the A549 model, in association with increased expression of hsa-miR-29b and reduced expression of antiapoptotic genes including DNA methyltransferase DNMT3B, commonly up-regulated in patients with NSCLC. Such inverse effects of combination therapy on DNMT3B and hsa-miR-29b expression were found in multiple models. Importantly, in the A549 model, hsa-miR-29b down-regulation of DMNT3b reduced promoter methylation of tumor suppressor genes such as Cell adhesion molecule 1 (CADM1), Ras associated (RalGDS/AF-6) domain family member 1 (RASSF1), and Fragile histidine triad gene (FHIT), increasing their expression.
  
  
  CONCLUSIONS
  These results offer a preclinical rationale for combining an EGFR antibody with cisplatin/gemcitabine for patients with NSCLC, and provide potential molecular biomarkers for tailoring therapy.
authors.affiliation: ImClone Systems, Eli Lilly and Company, New York, NY, USA. selda.samakoglu@imclone.com
authors.forename: Selda
authors.initials: S
authors.lastname: Samakoglu
authors.forename: Dhanvanthri S
authors.initials: DS
authors.lastname: Deevi
authors.forename: Huiling
authors.initials: H
authors.lastname: Li
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.forename: Mary
authors.initials: M
authors.lastname: Murphy
authors.forename: Channa
authors.initials: C
authors.lastname: Bao
authors.forename: Rajiv
authors.initials: R
authors.lastname: Bassi
authors.forename: Marie
authors.initials: M
authors.lastname: Prewett
authors.forename: James R
authors.initials: JR
authors.lastname: Tonra
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D016000:Cluster Analysis; D019175:DNA Methylation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; D066246:ErbB Receptors; D002945:Cisplatin; D000093542:Gemcitabine