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

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.

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

“…Consistently, patients with stable disease (SD) or an overall response (OR) to CTX therapy displayed lower IL-1R1 expression than the non-responding patients ( Figure 1 ). In line with our previous work [ 26 ], we conclude that increased expression of both IL-1 ligands (IL-1A and IL-1B) and receptor (IL-1R1) is associated with resistance to EGFR targeted therapy.…”

“…Several clinical studies indicate that overexpression of inflammatory cytokines, such as IL-1, IL8, IL6 or CXCL1, correlates with cancer progression and decreased response to EGFR targeting therapy [ 25 , 27 ]. We previously reported that the abundance of IL-1 cytokines predicts sensitivity to EGFR blockage [ 26 ]. To further assess the clinical relevance of our results, we explored whether the receptor for IL-1, namely IL-1R1, was enriched in tumors from patients exhibiting attenuated response to anti-EGFR antibodies.…”

“…In this vein, we previously reported that activation of a module of inflammatory cytokines, including IL1A , IL1B and IL8 , was associated with impaired therapeutic efficacy in a cohort of xenopatients treated with cetuximab (CTX) [ 25 , 26 , 27 ]. The current work investigated a possible causative role of secreted IL-1 cytokines in impairing response to CTX.…”

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…Benefits are the same for both wild-type and mutant KRAS tumors (234). It would be interesting to see the performance of combination cetuximab with CD73 inhibitors in preclinical CRC studies considering that inflammation is a mechanism of resistance to cetuximab (259). In melanoma, combination BRAF and MEK inhibitors with an A2AR antagonist induces significant tumor control in preclinical studies (41).…”

Oncogenic growth factor signaling mediating tumor escape from cellular immunity

“…Upregulation of this alternative pathway was postulated as an escape mechanism of erlotinib-resistant cells a view that was further supported by sensitization of these cells to erlotinib by tocilizumab mediated IL-6 receptor inhibition (50). Gelfo et al showed that activation of the EGFR in colorectal cancer cell lines mediated secretion of proinflammatory cytokines IL-1α, IL-1β and IL-8, which were associated with a cetuximab resistant phenotype in vitro ( 51 ) . Likewise, HER2 activation in breast cancer cell lines has been reported to induce secretion of proinflammatory cytokines IL-8 and CXCL1 (GRO) that were downregulated by gefitinib treatment, furthermore, circulating levels of IL-8 and CXCL1 in breast cancer patients highly correlated with HER2 expression (52).…”