A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy.
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.
['Gelfo|Valerio|V|0000-0001-9312-8406', 'Mazzeschi|Martina|M|', 'Grilli|Giada|G|', 'Lindzen|Moshit|M|', 'Santi|Spartaco|S|0000-0001-9856-7053', "D'Uva|Gabriele|G|0000-0001-9622-9288", 'Győrffy|Balázs|B|', 'Ardizzoni|Andrea|A|', 'Yarden|Yosef|Y|', 'Lauriola|Mattia|M|']
resistance cetuximab MAPK consensus molecular subtype colon cancer colonspheres inflammation