title: A module of inflammatory cytokines defines resistance of colorectal cancer to EGFR inhibitors.
abstract: Epidermal Growth Factor Receptor (EGFR) activates a robust signalling network to which colon cancer tumours often become addicted. Cetuximab, one of the monoclonal antibodies targeting this pathway, is employed to treat patients with colorectal cancer. However, many patients are intrinsically refractory to this treatment, and those who respond develop secondary resistance along time. Mechanisms of cancer cell resistance include either acquisition of new mutations or non genomic activation of alternative signalling routes. In this study, we employed a colon cancer model to assess potential mechanisms driving resistance to cetuximab. Resistant cells displayed increased ability to grow in suspension as colonspheres and this phenotype was associated with poorly organized structures. Factors secreted from resistant cells were causally involved in sustaining resistance, indeed administration to parental cells of conditioned medium collected from resistant cells was sufficient to reduce cetuximab efficacy. Among secreted factors, we report herein that a signature of inflammatory cytokines, including IL1A, IL1B and IL8, which are produced following EGFR pathway activation, was associated with the acquisition of an unresponsive phenotype to cetuximab in vitro. This signature correlated with lack of response to EGFR targeting also in patient-derived tumour xenografts. Collectively, these results highlight the contribution of inflammatory cytokines to reduced sensitivity to EGFR blockade and suggest that inhibition of this panel of cytokines in combination with cetuximab might yield an effective treatment strategy for CRC patients refractory to anti-EGFR targeting.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.|Center for Applied Biomedical Research (CRBA) S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Gelfo
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Rodia
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Pucci
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Dall'Ora
authors.affiliation: Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy.|Laboratory of Musculoskeletal Cell Biology, IOR-IRCCS, Bologna, Italy.
authors.forename: Spartaco
authors.initials: S
authors.lastname: Santi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Solmi
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Lee
authors.initials: L
authors.lastname: Roth
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Moshit
authors.initials: M
authors.lastname: Lindzen
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.|Center for Applied Biomedical Research (CRBA) S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonafè
authors.affiliation: Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), IRCCS, Department of Oncology, University of Torino, Candiolo, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Caramelli
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Pier-Luigi
authors.initials: PL
authors.lastname: Lollini
authors.affiliation: Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), IRCCS, Department of Oncology, University of Torino, Candiolo, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
authors.affiliation: Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: D'Uva
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.|Center for Applied Biomedical Research (CRBA) S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Lauriola
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology* / Q000627:therapeutic use; D018938:Caco-2 Cells; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D018613:Microscopy, Confocal; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C508606:CXCL8 protein, human; C508584:IL1A protein, human; C508585:IL1B protein, human; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: EGFR; cetuximab; colon cancer; resistance; transcriptional response