MTAP Deficiency-Induced Metabolic Reprogramming Creates a Vulnerability to Cotargeting De Novo Purine Synthesis and Glycolysis in Pancreatic Cancer

  • Cancer Res. 2021 Oct 1;81(19):4964-4980. doi: 10.1158/0008-5472.CAN-20-0414.
Qiangsheng Hu   #  1  2  3  4 ,  Yi Qin   #  1  2  3  4  5 ,  Shunrong Ji   #  1  2  3  4 ,  Xiuhui Shi   #  6 ,  Weixing Dai  5 ,  Guixiong Fan  1  2  3  4 ,  Shuo Li  3 ,  Wenyan Xu  1  2  3  4 ,  Wensheng Liu  1  2  3  4 ,  Mengqi Liu  1  2  3  4 ,  Zheng Zhang  1  2  3  4 ,  Zeng Ye  1  2  3  4 ,  Zhijun Zhou  6 ,  Jingxuan Yang  6 ,  Qifeng Zhuo  1  2  3  4 ,  Xianjun Yu  1  2  3  4 ,  Min Li  7 ,  Xiaowu Xu  8  2  3  4
Affiliations
  • 1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3. Shanghai Pancreatic Cancer Institute, Shanghai, China.
  • 4. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
  • 5. Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 6. Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • 7. Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. [email protected] [email protected].
  • 8. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. [email protected] [email protected].
  • # Contributed equally.
PMID: 34385182 DOI: 10.1158/0008-5472.CAN-20-0414
Abstract

Methylthioadenosine Phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20% to 30% of pancreatic Cancer. Our previous study revealed that MTAP deficiency indicates a poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion-mediated metabolic reprogramming enhanced glycolysis and de novo purine synthesis in pancreatic Cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF1α) protein via posttranslational phosphorylation. RIO Kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF1α to regulate its stability. In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) and the de novo purine synthesis inhibitor l-alanosine synergized to kill MTAP-deficient pancreatic Cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic Cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease. SIGNIFICANCE: This study demonstrates that MTAP status impacts glucose and purine metabolism, thus identifying multiple novel treatment options against MTAP-deficient pancreatic Cancer.

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