Targeting UBE2T potentiates gemcitabine efficacy in pancreatic cancer by regulating pyrimidine metabolism and replication stress

  • Gastroenterology. 2023 Feb 24;S0016-5085(23)00164-6. doi: 10.1053/j.gastro.2023.02.025.
Xiangyan Jiang  1 ,  Yong Ma  1 ,  Tao Wang  1 ,  Huinian Zhou  1 ,  Keshen Wang  1 ,  Wengui Shi  2 ,  Long Qin  2 ,  Junhong Guan  2 ,  Lianshun Li  1 ,  Bo Long  1 ,  Jianli Wang  3 ,  Xiaoying Guan  4 ,  Huili Ye  2 ,  Jing Yang  2 ,  Zeyuan Yu  1 ,  Zuoyi Jiao  5
Affiliations
  • 1. Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, China.
  • 2. Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, China.
  • 3. Department of Head and Neck Surgery, Gansu Provincial Cancer Hospital, Lanzhou, Gansu 730050, China.
  • 4. Department of Pathology, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, China.
  • 5. Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, China; Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, China. Electronic address: [email protected].
PMID: 36842710 DOI: 10.1053/j.gastro.2023.02.025
Abstract

Background & aims: Although small patient subsets benefit from current targeted strategies or immunotherapy, gemcitabine remains the first-line drug for pancreatic Cancer (PC) treatment. However, gemcitabine resistance is widespread and compromises long-term survival. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a potential therapeutic target to combat gemcitabine resistance in PC.

Methods: Proteomics and metabolomics were combined to examine the effect of UBE2T on pyrimidine metabolism remodeling. Spontaneous PC mice (LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre; KPC) with Ube2t-conditional knockout, organoids, and large-scale clinical samples were used to determine the effect of UBE2T on gemcitabine efficacy. Organoids, patient-derived xenografts (PDX), and KPC mice were used to examine the efficacy of the combination of a UBE2T inhibitor and gemcitabine.

Results: Spontaneous PC mice with Ube2t deletion had a marked survival advantage following gemcitabine treatment, and UBE2T levels were positively correlated with gemcitabine resistance in clinical patients. Mechanistically, UBE2T catalyzes RING1-mediated ubiquitination of p53 and relieves the transcriptional repression of RRM1 and RRM2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress. Additionally, high-throughput compound library screening using organoids identified pentagalloylglucose (PGG) as a potent UBE2T inhibitor and gemcitabine sensitizer. The combination of gemcitabine and PGG diminished tumor growth in PDX models and prolonged long-term survival in spontaneous PC mice.

Conclusions: Collectively, UBE2T-mediated p53 degradation confers PC gemcitabine resistance by promoting pyrimidine biosynthesis and alleviating replication stress. This study offers an opportunity to improve PC survival by targeting UBE2T and develop a promising gemcitabine sensitizer in clinical translation setting.

Keywords
Gemcitabine Resistance; Pancreatic Cancer; Pyrimidine Metabolism; Replication Stress; UBE2T.
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