Abstract 1986: IRAK1 augments cancer stemness and drug resistance via the AP-1/AKR1B10 signaling cascade in hepatocellular carcinoma

Abstract Frequent relapse and drug resistance can be attributed to the existence of tumor-initiating cells (T-ICs) within the tumor bulk. From transcriptome sequencing of 16 pairs of clinical HCC samples, we found that Interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway was significantly upregulated in hepatocellular carcinoma (HCC). IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patents survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also found to be consistently upregulated. We demonstrated that IRAK1 regulates liver T-IC properties, including self-renewal, tumorigenicity and liver T-IC marker expression. IRAK1 inhibition sensitized the HCC cells to doxorubicin and sorafenib treatment in vitro through the suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver T-IC populations. Through RNA sequencing analysis by comparing gene expression profiles between IRAK1-knockdown and control cells, we identified Aldo-Keto Reductase Family 1 Member 10 (AKR1B10) as a novel downstream target of IRAK1. Clinically, AKR1B10 was found to be overexpressed in HCC, which was significantly correlated with IRAK1 expression. Functional analysis demonstrated that knockdown of AKR1B10 negated the IRAK1-induced T-IC functions via modulation of the AP-1 complex. Using an HCC xenograft model, we found that an IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed the tumor growth. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC. Citation Format: Bowie Yik Ling Cheng, Doris Hoi Wing Leung, Eunice Yuen Ting Lau, Irene Oi Lin Ng, Kin Wah Lee. IRAK1 augments cancer stemness and drug resistance via the AP-1/AKR1B10 signaling cascade in hepatocellular carcinoma [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 1986.