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

Publié dans: CELL METABOLISM, 2019, 29 (6), pp.1243+. ⟨10.1016/j.cmet.2019.02.002⟩

Auteurs: Johanna Chiche, Julie Reverso-Meinietti, Annabelle Mouchotte, Camila Rubio-Patino, Rana Mhaidly, Elodie Villa, Jozef P. Bossowski, Emma Proics, Manuel Grima-Reyes, Agnes Paquet, Konstantina Fragaki, Sandrine Marchetti, Josette Briere, Damien Ambrosetti, Jean-Francois Michiels, Thierry Jo Molina, Christiane Copie-Bergman, Jacqueline Lehmann-Che, Isabelle Peyrottes, Frederic Peyrade, Eric De Kerviler, Bruno Taillan, Georges Garnier, Els Verhoeyen, Veronique Paquis-Flucklinger, Laetitia Shintu, Vincent Delwail, Celine Delpech-Debiais, Richard Delarue, Andre Bosly, Tony Petrella, Gabriel Brisou, Bertrand Nadel, Pascal Barbry, Nicolas Mounier, Catherine Thieblemont, Jean-Ehrland Ricci

Résumé

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.

Lien vers Pubmed [PMID] – 30827861

Lien vers HAL – hal-03400697

Lien vers le DOI – 10.1016/j.cmet.2019.02.002