Type Ii Interleukin 1 Receptor Modulated Setbp-1/Set/Pp2a/P-Erk Signaling Reduces The Therapeutic Activity Of Regorafenib Against Human Colorectal Cancer Cells

Regorafenib, a newly approved multi-kinase inhibitor by US FDA, has recently demonstrated overall survival benefits in late-stage colorectal cancer (CRC) patients. We have preliminarily observed that the expression type II interleukin 1 receptor (IL1R2), an IL-1 decoy receptor, was closely associated with regorafenib resistance in human CRC cells. We also found that IL1R2 expression was associated with poor prognosis and 5-year survival of CRC patients. In this study, we conducted experiments to elucidate the mechanisms underlying which IL1R2 is involved in regorafenib resistance. We first demonstrated that silencing of IL1R2 in HT29 cells overcame its resistance to regorafenib, whereas ectopic expression of IL1R2 in HCT116 cells reduced its sensitivity to regorafenib in either in vitro or in vivo assay systems. In addition, we established regorafenib-resistant DLD-1 cells (DLD-1-R) by long-term culturing DLD-1 cells in the presence of regorafenib, and we observed that protein expression of IL1R2 was increased in DLD-1-R cells compared to the parental DLD-1 cells. Furthermore, our results showed that IL1R2 expression was positively associated with p-ERK levels, which are crucial for survival of cancer cells. Pretreatment of HT29, IL1R2-overexpressing HCT116, and DLD-1-R cells with MEK/ERK inhibitor U0126 significantly reversed their regorafenib resistance in in vitro and in vivo systems. Mechanistically, we revealed that increased p-ERK levels in IL1R2-overexpressing cells were due to the decrease of PP2A activity instead of its expression levels. Since PP2A is a phosphatase of ERK, we further demonstrated that IL1R2 mediated through transcriptionally enhancing the expression of SETBP-1. The formation of SETBP-1/SET/PP2A complex decreased the activity of PP2A. Taken together, our present study identified IL1R2 was a potential prognostic and staging biomarker of CRC patients. Significantly, we also demonstrated a new molecular mechanism involved in regorafenib resistance and the combination of regorafenib and MEK/ERK inhibitor is a rationale regime to overcome regorafenib resistance in CRC patients. Citation Format: Ai-Chung Mar, Chun-Ho Chu, Shung-Haur Yang, Jeng-Kai Jiang, Chung-Wai Shiau, Te-Chang Lee. Type II interleukin 1 receptor-modulated SETBP-1/SET/PP2A/p-ERK signaling reduces the therapeutic activity of regorafenib against human colorectal cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 313.