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

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

Automated summary

This study investigates the metabolic characteristics of pancreatic ductal adenocarcinomas (PDAC) and identifies two subtypes based on glucose and lipid metabolism levels. Glucomet-PDAC, characterized by high glucose metabolism, exhibits higher chemotherapy resistance and worse prognosis compared to lipomet-PDAC with high lipid metabolism. The study reveals the role of the GLUT1/ALDOB/G6PD axis in inducing chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Inhibition of GLUT1 or G6PD enhances chemotherapy response in glucomet-PDAC.