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Cell Metab ; 29(6): 1243-1257.e10, 2019 06 04.
Article in English | MEDLINE | ID: mdl-30827861

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.


Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Glyceraldehyde-3-Phosphate Dehydrogenases/genetics , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/metabolism , Adult , Aged , Aged, 80 and over , Animals , Antimetabolites, Antineoplastic/administration & dosage , Cells, Cultured , Cohort Studies , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism , HEK293 Cells , Humans , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Prednisone/therapeutic use , Prognosis , Retrospective Studies , Rituximab/therapeutic use , Treatment Outcome , Vincristine/therapeutic use , Young Adult
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