2. Academic Validation
  3. Targeting UBE2T potentiates gemcitabine efficacy in pancreatic cancer by regulating pyrimidine metabolism and replication stress

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

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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