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

• DOI: 10.1016/j.cmet.2019.02.002
• Publication Date: 2019-02-28T15:48:15Z
• Authors: Johanna Chiche; Julie Reverso-Mei...; Annabelle Mouchotte; Camila Rubio-Patiño; Rana Mhaidly; Elodie Villa; Jozef P. Bossowski; Emma Proics; Manuel Grima-Reyes; Agnès Paquet; Konstantina Fragaki; Sandrine Marchetti; Josette Briere; Damien Ambrosetti; Jean-François Mic...; Thierry Jo Molina; Christiane Copie-...; Jacqueline Lehman...; Isabelle Peyrottes; Frederic Peyrade; Eric de Kerviler; Bruno Taillan; Georges Garnier; Els Verhoeyen; Véronique Paquis-...; Laetitia Shintu; Vincent Delwail; Celine Delpech-De...; Richard Delarue; André Bosly; Tony Petrella; Gabriel Brisou; Bertrand Nadel; Pascal Barbry; Nicolas Mounier; Catherine Thieble...; Jean-Ehrland Ricci
• Keywords: Adult; Male; 0301 basic medicine; Antimetabolites, Antineoplastic; Mice, Transgenic; Gene Expression Regulation, Enzymologic; Cohort Studies; Young Adult; Mice; 03 medical and health sciences; Antineoplastic Combined Chemotherapy Protocols; Animals; Humans; Cyclophosphamide; Cells, Cultured; Retrospective Studies; Aged; Aged, 80 and over; GAPDH; Glyceraldehyde-3-Phosphate Dehydrogenases; OxPhos; Middle Aged; glycolysis; Prognosis; L-asparaginase; 3. Good health; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; Treatment Outcome; HEK293 Cells; Vincristine; R-CHOP; Doxorubicin; DLBCL; mTOR; [SDV.IMM]Life Sciences [q-bio]/Immunology; Prednisone; Female; Lymphoma, Large B-Cell, Diffuse; Rituximab; predictive marker

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 GAPDHlow 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 GAPDHlow B cells and improve GAPDHlow B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDHhigh B cell lymphomas. Ultimately, we selected four GAPDHlow 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.