Aberrant activation of the NF-κB transcription factors is a major molecular mechanism that contributes to the aggressive behavior and treatment resistance of colorectal cancer (CRC). Understanding how these factors are activated will provide novel therapeutic opportunities to improve treatment response and outcome of CRC patients. In the present study, we showed that the Interleukin-1 Receptor-Associated Kinases 1 and 4 (IRAK1 and IRAK4) are constitutively activated by phosphorylation in a majority of CRC cell lines and patients samples. Notably, we observe significant positive correlation between phospho-IRAK4 and phospho-NF-kb/p65 staining by immunohistochemistry in patient CRC samples. Moreover, we showed that pharmacologic IRAK4 inhibitors dose-dependently suppressed phosphorylated -IRAK1, -IRAK4 and -IKKa/b by western blots, as well as significantly reducing NF-κB-driven luciferase activity in CRC cells. Furthermore, IRAK4 inhibitor dose dependently inhibit colony formation and anchorage-independent (AI) growth of CRC cells in soft agar. In three CRC cell lines, we observed various degrees of synergism between IRAK4 inhibitors and each chemotherapeutic agents including 5-FU, oxaliplatin and irinotecan, mainly through induction of apoptosis. Lastly, we showed that IRAK4 inhibitor augments the therapeutic effect of 5-FU and oxaliplatin in nude mice bearing CRC xenografts. Together, our data established IRAK4 kinase inhibitors as a promising novel class of targeted agent in CRC.

Citation Format: Qiong Li, Lin Li, Daoxiang Zhang, Hongmei Jiang, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim. Constitutive IRAK4 activation contributes to NF-κB activity and chemoresistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1941.