Faculty, Staff and Student Publications
Publication Date
6-1-2023
Journal
Haematologica
Abstract
Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma characterized by frequent relapses. The development of resistance to ibrutinib therapy remains a major challenge in MCL. We previously showed that glutaminolysis is associated with resistance to ibrutinib. In this study, we confirmed that glutaminase (GLS), the first enzyme in glutaminolysis, is overexpressed in ibrutinib-resistant MCL cells, and that its expression correlates well with elevated glutamine dependency and glutaminolysis. Furthermore, we discovered that GLS expression correlates with MYC expression and the functioning of the glutamine transporter ASCT2. Depletion of glutamine or GLS significantly reduced cell growth, while GLS overexpression enhanced glutamine dependency and ibrutinib resistance. Consistent with this, GLS inhibition by its specific inhibitor telaglenastat suppressed MCL cell growth both in vitro and in vivo. Moreover, telaglenastat showed anti-MCL synergy when combined with ibrutinib or venetoclax in vitro, which was confirmed using an MCL patient-derived xenograft model. Our study provides the first evidence that targeting GLS with telaglenastat, alone or in combination with ibrutinib or venetoclax, is a promising strategy to overcome ibrutinib resistance in MCL.
Keywords
Humans, Adult, Drug Resistance, Neoplasm, Cell Line, Tumor, Glutaminase, Lymphoma, Mantle-Cell, Glutamine, Neoplasm Recurrence, Local, Enzyme Inhibitors
DOI
10.3324/haematol.2022.281538
PMID
36420799
PMCID
PMC10230437
PubMedCentral® Posted Date
11-24-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Hematology Commons, Hemic and Lymphatic Diseases Commons, Medical Genetics Commons, Neoplasms Commons, Oncology Commons