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

Valerio Gelfo, Martina Mazzeschi, Giada Grilli, Moshit Lindzen, Spartaco Santi, Gabriele D'Uva, Balázs Győrffy, Andrea Ardizzoni, Yosef Yarden, Mattia Lauriola

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalCancers
Volume10
Issue number10
DOIs
Publication statusPublished - Sep 26 2018

Keywords

  • MAPK
  • cetuximab
  • colon cancer
  • colonspheres
  • consensus molecular subtype
  • inflammation
  • 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. (2018). A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy. Cancers, 10(10), 1-16. https://doi.org/10.3390/cancers10100355