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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

Johanna Chiche 1 Julie Reverso-Meinietti 2 Annabelle Mouchotte Camila Rubio-Patino 3 Rana Mhaidly 3 Elodie Villa 3 Jozef P. Bossowski Emma Proics 1 Manuel Grima-Reyes Agnes Paquet 4 Konstantina Fragaki 5 Sandrine Marchetti 3 Josette Briere 6 Damien Ambrosetti 7 Jean-Francois Michiels 7 Thierry Jo Molina 8 Christiane Copie-Bergman 9 Jacqueline Lehmann-Che 10 Isabelle Peyrottes 11 Frederic Peyrade 12 Eric Kerviler Bruno Taillan Georges Garnier 13 Els Verhoeyen 14 Veronique Paquis-Flucklinger 5 Laetitia Shintu 15 Vincent Delwail 16, 17 Celine Delpech-Debiais 17 Richard Delarue 18 Andre Bosly 19 Tony Petrella 20 Gabriel Brisou 21 Bertrand Nadel 21 Pascal Barbry 22 Nicolas Mounier 23 Catherine Thieblemont 24 Jean-Ehrland Ricci 25
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 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.
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Submitted on : Monday, October 25, 2021 - 10:23:12 AM
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Johanna Chiche, Julie Reverso-Meinietti, Annabelle Mouchotte, Camila Rubio-Patino, Rana Mhaidly, et al.. GAPDH Expression Predicts the Response to R-CHOP, the Tumor Metabolic Status, and the Response of DLBCL Patients to Metabolic Inhibitors. CELL METABOLISM, 2019, 29 (6), pp.1243+. ⟨10.1016/j.cmet.2019.02.002⟩. ⟨hal-02359440⟩

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