Senescence-associated reprogramming induced by interleukin-1 impairs response to EGFR neutralization

Abstract

Background EGFR targeting is currently the main treatment strategy for metastatic colorectal cancer (mCRC). Results of different clinical trials show that patients with wild-type KRAS and BRAF benefit from anti-EGFR monoclonal antibodies (moAbs) cetuximab (CTX) or panitumumab. Unfortunately, despite initial response, patients soon became refractory. Tumor heterogeneity and multiple escaping routes have been addressed as the main culprit, and, behind genomic alterations already described, changes in signaling pathways induced by drug pressure are emerging as mechanisms of acquired resistance. We previously reported an association between reduced sensitivity to CTX and increased expression of IL-1. However, how IL-1 mediates CTX resistance in mCRC is still unclear. Methods Under CTX treatment, the upregulation of IL-1R1 expression and a senescence program in sensitive colorectal cancer (CRC) cell lines is examined over time using qPCR, immunoblotting, and immunofluorescence. Results In sensitive CRC cells, IL-1 appeared responsible for a CTX-mediated G0 phase arrest. On the contrary, CTX-resistant CRC cells (CXR) maintained high mRNA levels of IL-1R1 and a post-senescence reprogramming, as indicated by increased SNAIL expression. Interestingly, treatment of CXR cells with a recombinant decoy, able to sequester the soluble form of IL-1, pushed CTX-resistant CRC cells back into a stage of senescence, thus blocking their proliferation. Our model suggests a trans-regulatory mechanism mediated by IL-1 on EGFR signaling. By establishing senescence and regulating EGFR activity and expression, IL-1 exposure ultimately bestows resistance. Conclusions To sum up, our findings point to the combined blockage of IL-1R and EGFR as a promising therapeutical approach to restore sensitivity to EGFR-targeting monoclonal antibodies.

IL-1 and senescence: Friends and foe of EGFR neutralization and immunotherapy

“…In our work we explored the effect of cetuximab in colorectal cancer in vitro models and the antibody was able to increase senescence markers. In addition, our investigation also revealed that cetuximab was acting by inducing the production of the pro-inflammatory cytokine IL-1 and released in the microenvironment ( Romaniello et al, 2022 ). Considering the known role of IL-1 in inducing senescence, is tempting to consider it as one of the mechanisms of action for CTX, that will achieve a cell cycle arrest by immediate autocrine production of IL-1 ( Figure 2 ).…”

“…These findings challenge the consolidated theory about senescence as the conclusion of the life cycle followed by permanent growth arrest, and unveil a dynamic post-senescence process, which represents a defy for therapeutical agents. Thus, the contemporary targeting of senescence by senotherapeutic drugs along with target therapy toward ERBB family members may boost the efficacy of future cancer treatment ( Zhu et al, 2015 ; Schafer et al, 2017 ; Ovadya and Krizhanovsky, 2018 ; Romaniello et al, 2022 ).…”

“…By creating a pro-inflammatory environment with immunosuppression function and by inducing DNA damage, they both contribute to the establishment of senescence in autocrine and paracrine manner. During this time, the increased levels of error-prone DNA polymerases allow cell cycle re-entry of drug-resistant mutagenic variants which ultimately converge for tumor relapse ( Kaplanov et al, 2019 ; Singh et al, 2021 ; Romaniello et al, 2022 ).…”

“…Previous observations from our laboratory shown that CRC cells exposed to monoclonal antibody anti-EGFR, displayed an increased expression of EMT markers and an array of cytokines, IL-1α, IL-1β and IL-8 ( Gelfo et al, 2016 ). Interestingly, the CTX-treated CRC cell line displayed a senescence phenotype, and conversely, IL-1 neutralization was able to revert the CTX-resistant cells into a senescence-mediated growth arrest ( Romaniello et al, 2022 ).…”

Multiomics analysis revealed the mechanisms related to the enhancement of proliferation, metastasis and EGFR-TKI resistance in EGFR-mutant LUAD with ARID1A deficiency

“…Small molecular inhibitors or monoclonal antibodies for EGFR signaling have been widely used for EGFR signaling-dependent malignancies [ 21 , 22 ]. A previous review [ 21 ] proposed the potential role of ARID1A as a novel biomarker for the response to EGFR-TKIs.…”