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Open AccessArticle

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

1
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
2
Centre for Applied Biomedical Research (CRBA), Bologna University Hospital Authority St. Orsola-Malpighi Polyclinic, 40138 Bologna, Italy
3
Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
4
Institute of Molecular Genetics, National Research Council of Italy, 40136 Bologna, Italy
5
IRCCS-Istitute Orthopaedic Rizzoli, 40136 Bologna, Italy
6
Scientific and Technology Pole, IRCCS MultiMedica, 20138 Milan, Italy
7
MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Magyar Tudósok körútja 2, 1117 Budapest, Hungary
8
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; https://doi.org/10.3390/cancers10100355
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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