GAPDH Expression Predicts the Response to R-CHOP, the Tumor Metabolic Status, and the Response of DLBCL Patients to Metabolic Inhibitors

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDH^low lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism (phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDH^low B cells and improve GAPDH^low B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDH^high B cell lymphomas. Ultimately, we selected four GAPDH^low DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients’ response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors. About 40% of diffuse large B cell lymphoma (DLBCL) patients are refractory to the combined immuno-chemotherapy (R-CHOP) standard of care. DLBCL is metabolically heterogeneous, and Chiche et al. show that low levels of GAPDH, which predict poor R-CHOP response, are associated with OxPhos metabolism, mTORC1 signaling, and glutaminolysis. Disruptors of these pathways improved GAPDH^low DLBCL response in mice and patients.