A novel role for interleukin 1 axis in the resistance to EGFR targeting antibody

Background Cetuximab (CTX) is a monoclonal antibody targeting the Epidermal Growth Factor Receptor (EGFR), which is commonly utilized to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, clinicians often observe a residual disease, with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous studies, performed with a cohort of 150 CRC xenopatients, associated poor response to CTX with increased abundance of a set of pro-inflammatory cytokines, including IL-1A, IL-1B and IL-8. IL-1 has been reported in the promotion of Senescence Associated Secretory Phenotype (SASP). Stemming from these observations, our current work aims to assess the effect of IL-1 pathway in CTX mediated senescence and resistance. Methods We employed a recombinant decoy (IL-1R1 TRAP), namely a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of IL1-receptor, with the ability to sequester IL1 directly from the medium. We generated stable clones expressing a functional IL-1R1 TRAP, and tested the effects on proliferation of cancer cells growing both as monolayer and as 3D colonospheres. Next, the action of IL-1R1 TRAP decoy on EGFR downstream signalling pathways has been evaluated by analyses of MAPK and AKT axes. Results The analysis of colorectal cancer patients' datasets revealed that high levels of IL-1 receptor correlate with poor survival, specifically for the consensus molecular subtype 1 (CMS1). Next, mCRC patients not responding to CTX blockage, display higher level of IL-1R1 compared to the responsive ones. Furthermore, we found that IL-1R1 inhibition leads to decreased proliferation of colorectal cancer cells as consequence of a dampened MAPK and AKT signalling activation. Mechanistically, we show that CTX leads to a post-senescent phenotype as detected by bgalactosidase, HP1-g and p21 markers and stemness traits. Conclusions We are currently working on dissecting the contribution of IL1 signalling in resistance to CTX, as a consequence of the post-senescent phenotype. We conclude that IL1 signalling inhibition may represent a new therapeutic strategy suitable for patients who acquired refractoriness to EGFR targeted antibody therapy.