TY - JOUR
T1 - Targeting glutaminase is therapeutically effective in ibrutinib-resistant mantle cell lymphoma
AU - Li, Lingzhi
AU - Nie, Lei
AU - Jordan, Alexa
AU - Cai, Qingsong
AU - Liu, Yang
AU - Li, Yijing
AU - Che, Yuxuan
AU - Vargas, Jovanny
AU - Chen, Zhihong
AU - Leeming, Angela
AU - Wang, Wei
AU - Yao, Yixin
AU - Wang, Michael
AU - Jiang, Vivian Changying
N1 - Publisher Copyright:
©2023 Ferrata Storti Foundation.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
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U2 - 10.3324/haematol.2022.281538
DO - 10.3324/haematol.2022.281538
M3 - Article
C2 - 36420799
AN - SCOPUS:85149694103
SN - 0390-6078
VL - 108
SP - 1616
EP - 1627
JO - Haematologica
JF - Haematologica
IS - 6
ER -