Oncotarget

Research Papers:

A module of inflammatory cytokines defines resistance of colorectal cancer to EGFR inhibitors

Valerio Gelfo, Maria Teresa Rodia, Michela Pucci, Massimiliano Dall’Ora, Spartaco Santi, Rossella Solmi, Lee Roth, Moshit Lindzen, Massimiliano Bonafè, Andrea Bertotti, Elisabetta Caramelli, Pier-Luigi Lollini, Livio Trusolino, Yosef Yarden, Gabriele D’Uva and Mattia Lauriola _

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Oncotarget. 2016; 7:72167-72183. https://doi.org/10.18632/oncotarget.12354

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Abstract

Valerio Gelfo1,2,*, Maria Teresa Rodia1,*, Michela Pucci1, Massimiliano Dall’Ora1, Spartaco Santi3,4, Rossella Solmi1, Lee Roth5, Moshit Lindzen5, Massimiliano Bonafè1,2, Andrea Bertotti6, Elisabetta Caramelli1, Pier-Luigi Lollini1, Livio Trusolino6, Yosef Yarden5, Gabriele D’Uva7,**, Mattia Lauriola1,2,**

1Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy

2Center for Applied Biomedical Research (CRBA) S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy

3Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy

4Laboratory of Musculoskeletal Cell Biology, IOR-IRCCS, Bologna, Italy

5Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

6Candiolo Cancer Institute-Fondazione del Piemonte per l’Oncologia (FPO), IRCCS, Department of Oncology, University of Torino, Candiolo, Italy

7Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy

*These authors have contributed equally to this work

**Co-last authors

Correspondence to:

Mattia Lauriola, email: mattia.lauriola@gmail.com

Keywords: EGFR, transcriptional response, colon cancer, resistance, cetuximab

Received: June 13, 2016    Accepted: September 21, 2016    Published: September 30, 2016

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.


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