Abstract 3683: Activation of purine anabolism creates a therapeutic vulnerability in hepatocellular carcinoma via m6A-mediated epitranscriptomic regulation

Abstract

Abstract Introduction Purines are building blocks for genomics and the abundance of purine nucleotides is controlled by purine synthesis and purine degradation. Imbalance of purine nucleotide pool in tumors has been shown, but how synthesis and degradation of purine integrates in tumors has not been well characterized. Hepatocellular carcinoma (HCC) is the most common liver cancer with a high mortality rate and limited treatments. Aberrant purine metabolism was observed in HCC, but the functional status of global purine metabolism in HCC and how that drive HCC fitness and therapeutic response remain unclear. Method HCC-specific purine metabolic changes were identified from the transcriptomic and metabolic data of tumor and paired non-tumor liver tissues obtained from 62 HCC patients from Thailand (discovery cohort) and validated in an additional 672 HCC with different race/ethnicities and etiologies. Correlation analysis of purine metabolic alteration and tumor-associated genomic, transcriptome and metabolome were conducted. The impacts of purine metabolism on HCC survival and therapeutic vulnerability were investigated. Biological functions of purine metabolic alterations were assessed in vitro and in vivo on multiple HCC cell lines. Results Using multi-omics integrative analyses, we found a tumor-specific activation of purine anabolism, induced by upregulation of purine de novo biosynthesis and inhibition of purine degradation, in HCC. A high purine anabolic status was associated with dysregulation of the DNA damage repairing (DDR) machinery in HCC, accompanied by unique somatic mutational signatures linked to patient prognosis. By examining drug responses to 180 molecular targeted agents in HCC cells, we found that increasing purine anabolism induced a therapeutic vulnerability of HCC to DDR targeting agents. Mechanistically, we found that excessive purine metabolites induced N6-methyladenosine (m6A) modification on DTL, a DDB1 cullin4 associated factor, thereby delaying the degradation of DTL mRNA transcriptomic remodeling of the DDR machinery and tumor fitness. Experimentally, we demonstrated that suppressing purine anabolism or exposing to DDR targeting agent, such as berzosertib, inhibited the growth of HCCs with high purine anabolism in vitro and in vivo. Conclusion Our study suggests that targeting purine anabolism or DDR may represent as attractive strategies in patients with high purine anabolic HCCs, and purine anabolic status could be a valuable biomarker to allocate systemic treatments for patients with advanced HCC. Citation Format: Man-Hsin Hung, Ching Wen Chang, Kathy Cheng Wang, Jittiporn Chaisaingmongkol, Mathuros Ruchirawat, Tim F. Greten, Xin Wei Wang. Activation of purine anabolism creates a therapeutic vulnerability in hepatocellular carcinoma via m6A-mediated epitranscriptomic regulation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3683.