title: Primary and acquired resistance of colorectal cancer cells to anti-EGFR antibodies converge on MEK/ERK pathway activation and can be overcome by combined MEK/EGFR inhibition.
abstract: OBJECTIVE
  The EGFR-independent activation of the RAS/RAF/MEK/MAPK pathway is one of the resistance mechanisms to cetuximab.
  
  
  METHODS
  We have evaluated, in vitro and in vivo, the effects of BAY 86-9766, a selective MEK1/2 inhibitor, in a panel of human colorectal cancer cell lines with primary or acquired resistance to cetuximab.
  
  
  RESULTS
  Among the colorectal cancer cell lines, five with a KRAS mutation (LOVO, HCT116, HCT15, SW620, and SW480) and one with a BRAF mutation (HT29) were resistant to the antiproliferative effects of cetuximab, whereas two cells (GEO and SW48) were highly sensitive. Treatment with BAY 86-9766 determined dose-dependent growth inhibition in all cancer cells, including two human colorectal cancer cells with acquired resistance to cetuximab (GEO-CR and SW48-CR), with the exception of HCT15 cells. Combined treatment with cetuximab and BAY 86-9766 induced a synergistic antiproliferative and apoptotic effects with blockade in the MAPK and AKT pathway in cells with either primary or acquired resistance to cetuximab. The synergistic antiproliferative effects were confirmed using other two selective MEK1/2 inhibitors, selumetinib and pimasertib, in combination with cetuximab. Moreover, inhibition of MEK expression by siRNA restored cetuximab sensitivity in resistant cells. In nude mice bearing established human HCT15, HCT116, SW48-CR, and GEO-CR xenografts, the combined treatment with cetuximab and BAY 86-9766 caused significant tumor growth inhibition and increased mice survival.
  
  
  CONCLUSIONS
  These results suggest that activation of MEK is involved in both primary and acquired resistance to cetuximab and the inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance in patients with colorectal cancer.
authors.affiliation: Authors' Affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Via S. Pansini 5, Naples, Italy tessy75@inwind.it.
authors.forename: Teresa
authors.initials: T
authors.lastname: Troiani
authors.affiliation: Authors' Affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Via S. Pansini 5, Naples, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Napolitano
authors.affiliation: Authors' Affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Via S. Pansini 5, Naples, Italy.
authors.forename: Donata
authors.initials: D
authors.lastname: Vitagliano
authors.affiliation: Authors' Affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Via S. Pansini 5, Naples, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Morgillo
authors.affiliation: Authors' Affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Via S. Pansini 5, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Capasso
authors.affiliation: Authors' Affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Via S. Pansini 5, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Sforza
authors.affiliation: Authors' Affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Via S. Pansini 5, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Nappi
authors.affiliation: Authors' Affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Via S. Pansini 5, Naples, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Ciardiello
authors.affiliation: Authors' Affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Via S. Pansini 5, Naples, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Authors' Affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Via S. Pansini 5, Naples, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Martinelli
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C544830:N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; D013449:Sulfonamides; D004159:Diphenylamine; C512478:EGFR protein, human; D066246:ErbB Receptors; D020930:MAP Kinase Kinase Kinases; D000068818:Cetuximab