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Open AccessArticle

A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
Centre for Applied Biomedical Research (CRBA), Bologna University Hospital Authority St. Orsola-Malpighi Polyclinic, 40138 Bologna, Italy
Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
Institute of Molecular Genetics, National Research Council of Italy, 40136 Bologna, Italy
IRCCS-Istitute Orthopaedic Rizzoli, 40136 Bologna, Italy
Scientific and Technology Pole, IRCCS MultiMedica, 20138 Milan, Italy
MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Magyar Tudósok körútja 2, 1117 Budapest, Hungary
Semmelweis University 2nd Dept. of Pediatrics, Tűzoltó utca 7–9, 1094 Budapest, Hungary
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2018, 10(10), 355;
Received: 30 July 2018 / Revised: 10 September 2018 / Accepted: 23 September 2018 / Published: 26 September 2018
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)
Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous study on CRC xenopatients associated poor response to CTX with increased abundance of a set of pro-inflammatory cytokines, including the interleukins IL-1A, IL-1B and IL-8. Stemming from these observations, our current work aimed to assess the role of IL-1 pathway activity in CTX resistance. We employed a recombinant decoy TRAP IL-1, a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of the IL-1-receptor (IL-1R1), able to sequester IL-1 directly from the medium. We generated stable clones expressing and secreting a functional TRAP IL-1 into the culture medium. Our results show that IL-1R1 inhibition leads to a decreased cell proliferation and a dampened MAPK and AKT axes. Moreover, CRC patients not responding to CTX blockage displayed higher levels of IL-1R1 than responsive subjects, and abundant IL-1R1 is predictive of survival in patient datasets specifically for the consensus molecular subtype 1 (CMS1). We conclude that IL-1R1 abundance may represent a therapeutic marker for patients who become refractory to monoclonal antibody therapy, while inhibition of IL-1R1 by TRAP IL-1 may offer a novel therapeutic strategy. View Full-Text
Keywords: cetuximab; colon cancer; inflammation; colonspheres; MAPK; consensus molecular subtype; resistance cetuximab; colon cancer; inflammation; colonspheres; MAPK; consensus molecular subtype; resistance
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Gelfo, V.; Mazzeschi, M.; Grilli, G.; Lindzen, M.; Santi, S.; D’Uva, G.; Győrffy, B.; Ardizzoni, A.; Yarden, Y.; Lauriola, M. A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy. Cancers 2018, 10, 355.

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