Molecular mechanisms of resistance to cetuximab mediated by IL-1 signaling

Cetuximab (CTX) is a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR), which is commonly employed to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, clinicians often observe a failure of the therapy with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous studies, employing a cohort of 150 CRC xenopatients, associated poor response to CTX with increase abundance of a set of inflammatory cytokines, namely IL-1, IL-1 and IL-8 (Gelfo et al., 2016). In the time frame of my first year of Ph.D, we found that in patients, undergoing CTX treatment, overexpression of IL-1 Receptor (IL-1R) correlates with reduced response. Stemming from these observations, we assumed that resistance to CTX is acquired, in a subset of CRC patients, through cell plasticity, as a consequent rewiring of signaling networks. Employing a recombinant decoy (IL1R-Fc) able to sequester IL-1 directly from the medium, our results show that IL1R decoy successfully dampens pSTAT3 activation along with MAPK and PI3K axes, thus decreasing proliferation and colon spheres formation. Furthermore, we report that IL1R abundance predicts disease relapse free survival in a cohort of 1700 colorectal cancer patients, and it appears associated to a specific subtype, namely the consensus molecular subtype 1 (CMS1). Our data therefore suggest that a loop mediated by the IL1 and its cognate receptor mediates CTX resistance in a specific subtype of colorectal cancer. Mechanistically, our preliminary data show that CTX treatment promotes an increase in inflammatory cytokines leading to a post-senescent phenotype, as detected by -galactosidase, HP1- and p21 markers