Preclinical Investigations of the Efficacy of the Glutaminase Inhibitor CB-839 Alone and in Combinations in Chronic Lymphocytic Leukemia

Authors

Natalia Timofeeva
Mary L Ayres
Natalia Baran
Janice M Santiago-O'Farrill
Gamze Bildik
Zhen Lu
Marina Konopleva
Varsha Gandhi

Publication Date

5-9-2023

Journal

Frontiers in Oncology

Abstract

INTRODUCTION: Chronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species.

METHODS: To investigate the

RESULTS: We found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839-treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in the oxygen consumption rate and depletion of the adenosine triphosphate pool and led to the inhibition of cell proliferation. In the cell lines, CB-839 combined with venetoclax or AZD-5991, but not with ibrutinib, demonstrated synergism with an increased apoptosis rate and cell proliferation inhibition. In the primary lymphocytes, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed.

DISCUSSION: Our findings suggest that CB-839 has limited efficacy in CLL treatment and shows limited synergy in combination with widely used CLL drugs.

Keywords

CLL - chronic lymphoblastic leukemia, BTK - Bruton’s tyrosine kinase, Bcl-2 inhibitor, Mcl-1 inhibitor, ibrutinib, venetoclax, glutamine (Gln) metabolism

Comments

Supplementary Materials

PMID: 37228498