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

Cell metabolism (2019-03-05)
Johanna Chiche, Julie Reverso-Meinietti, 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 Michiels, Thierry Jo Molina, Christiane Copie-Bergman, Jacqueline Lehmann-Che, Isabelle Peyrottes, Frederic Peyrade, Eric de Kerviler, Bruno Taillan, Georges Garnier, Els Verhoeyen, Véronique Paquis-Flucklinger, Laetitia Shintu, Vincent Delwail, Celine Delpech-Debiais, Richard Delarue, André Bosly, Tony Petrella, Gabriel Brisou, Bertrand Nadel, Pascal Barbry, Nicolas Mounier, Catherine Thieblemont, Jean-Ehrland Ricci
ABSTRACT

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.

MATERIALS
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