Targeting glutaminase is therapeutically effective in ibrutinib-resistant mantle cell lymphoma
Lingzhi Li,
Lei Nie,
Alexa Jordan,
Qingsong Cai,
Yang Liu,
Yijing Li,
Yuxuan Che,
Jovanny Vargas,
Zhihong Chen,
Angela Leeming,
Wei Wang,
Yixin Yao,
Michael Wang,
Vivian Changying Jiang
Affiliations
Lingzhi Li
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Lei Nie
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Alexa Jordan
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Qingsong Cai
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Yang Liu
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Yijing Li
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Yuxuan Che
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Jovanny Vargas
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Zhihong Chen
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Angela Leeming
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Wei Wang
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Yixin Yao
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
Michael Wang
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center
Vivian Changying Jiang
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
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.
