Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer

• DOI: 10.1016/j.xcrm.2023.101162
• Publication Date: 2023-08-18T14:32:32Z
• Authors: Yunguang Li; Shijie Tang; Xiaohan Shi; Jingwen Lv; Xueyuan Wu; Yehan Zhang; Huan Wang; Juan He; Yiqin Zhu; Yi Ju; Yajuan Zhang; Shiwei Guo; Weiwei Yang; Huiyong Yin; Luonan Chen; Dong Gao; Gang Jin
• Keywords: Pancreatic Neoplasms; Glucose Transporter Type 1; Glucose; Fructose-Bisphosphate Aldolase; Humans; Glucosephosphate Dehydrogenase; Article; 3. Good health; Carcinoma, Pancreatic Ductal

Metabolic reprogramming is known as an emerging mechanism of chemotherapy resistance, but the metabolic signatures pancreatic ductal adenocarcinomas (PDACs) remain unclear. Here, we characterize metabolomic profile PDAC organoids and classify them into glucomet-PDAC (high glucose metabolism levels) lipomet-PDAC lipid levels). Glucomet-PDACs are more resistant to than lipomet-PDACs, patients with have a worse prognosis. Integrated analyses reveal that GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces resistance by remodeling in glucomet-PDAC. Increased glycolytic flux, G6PD activity, pyrimidine biosynthesis identified high GLUT1 low ALDOB expression, these phenotypes could be reversed inhibiting expression or increasing expression. Pharmacological inhibition enhances response Our findings uncover potential heterogeneity related differences sensitivity develop promising pharmacological strategy for chemotherapy-resistant through combination GLUT1/ALDOB/G6PD inhibitors.