title: Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models.
abstract: OBJECTIVE
  The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance.
  
  
  METHODS
  We have investigated in three models of highly epidermal growth factor receptor (EGFR)-dependent colorectal cancer xenografts, the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab, after cytotoxic treatment induction with irinotecan plus cetuximab.
  
  
  RESULTS
  SW48, LIM 1215, and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab. The combined treatment induced a significant reduction of tumor size. A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab, mice were randomly assigned to one of the following treatments: control, cetuximab, regorafenib, a selective PIK3CA inhibitor (PIK3CAi), a selective MEK inhibitor (MEKi), and/or the combination of each inhibitor with cetuximab. The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth. This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival. Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways. Moreover, in the cetuximab plus MEKi-treated SW48 xenograft group, KRAS mutations as a mechanism of acquired resistance were detected in 25% of cases compared with 75% KRAS mutations in the MEKi-treated group.
  
  
  CONCLUSIONS
  A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab.
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy. tessy75@inwind.it.
authors.forename: Teresa
authors.initials: T
authors.lastname: Troiani
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Napolitano
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Martini
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Martinelli
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cardone
authors.affiliation: Cell Biology and Biotherapy Unit, National Cancer Institute "Fondazione Giovanni Pascale," Naples, Italy. Pharmacogenomic Laboratory, INT-Fondazione Pascale-Centro di Ricerche Oncologiche di Mercogliano (CROM), Mercogliano (AV), Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Normanno
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Donata
authors.initials: D
authors.lastname: Vitagliano
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Morgillo
authors.affiliation: Pharmacogenomic Laboratory, INT-Fondazione Pascale-Centro di Ricerche Oncologiche di Mercogliano (CROM), Mercogliano (AV), Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fenizia
authors.affiliation: Pharmacogenomic Laboratory, INT-Fondazione Pascale-Centro di Ricerche Oncologiche di Mercogliano (CROM), Mercogliano (AV), Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Lambiase
authors.affiliation: Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, Naples, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Formisano
authors.affiliation: Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianco
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Ciardiello
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D002470:Cell Survival; D000068818:Cetuximab / Q000008:administration & dosage*; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D000077146:Irinotecan; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: C544830:N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; D013449:Sulfonamides; D000077146:Irinotecan; D004159:Diphenylamine; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D020930:MAP Kinase Kinase Kinases; D000068818:Cetuximab; D002166:Camptothecin