title: Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab.
abstract: OBJECTIVE
  In colorectal cancer, the activation of the intracellular RAS-RAF and PIK3CA-AKT pathways has been implicated in the resistance to anti-EGFR mAbs. We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resistance.
  
  
  METHODS
  We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximab-sensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR).
  
  
  RESULTS
  Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximab-resistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation.
  
  
  CONCLUSIONS
  The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients.
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: Sezione di Farmacologia, Dipartimento di Medicina Sperimentale "L.Donatelli," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rinaldi
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: Sezione di Farmacologia, Dipartimento di Medicina Sperimentale "L.Donatelli," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Donniacuo
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Sperimentale "L.Donatelli," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Liberato
authors.initials: L
authors.lastname: Berrino
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: Immunologia Clinica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Giusy
authors.initials: G
authors.lastname: Barra
authors.affiliation: Immunologia Clinica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Palma
authors.affiliation: Dipartimento di Scienze Biomediche Avanzate, Universita Federico II, Napoli, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Merolla
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
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
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab