Dihydroorotate dehydrogenase inhibition acts synergistically with tyrosine kinase inhibitors to induce apoptosis of mantle cell lymphoma cells

eJHaem

article

May Eriksen-Gjerstad¹  Ida Tveit Karlsen¹  Zinayida Fandalyuk¹  Susanne Benjaminsen¹  Fanny Baran-Marszak²  Bela Papp³  Frederick Locke⁵  Marcus Ladds⁶  Andrés Pastor-Fernández⁶  Pascal Gelebart¹  Emmet Mc Cormack¹ 

[1] Department of Clinical Science, University of Bergen;Inserm U978, Université Paris-13;Institut National de la Santé et de la Recherche Médicale, UMR U976, Institut de Recherche Saint-Louis, Hôpital Saint-Louis, Université de Paris;CEA, DRF-Institut Francois Jacob, Department of Hemato-Immunology Research, Hôpital Saint-Louis;Department of Blood and Marrow Transplant and Cellular Therapy, Moffit Cancer Centre;Department of Microbiology, Tumor and Cell Biology ,(MTC), Karolinska Institutet;SciLifeLab, Department of Microbiology, Tumor and Cell Biology ,(MTC), Karolinska Institutet;Department of Quality and Development, Hospital Pharmacies Enterprise in Western Norway;Centre for Cancer Biomarkers CCBIO

关键词: apoptosis;    DHODH;    mantle cell lymphoma;    targeted therapy;   

DOI  :  10.1002/jha2.434

来源: Wiley

【 摘 要 】

Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that remains incurable with the treatment options available today. In the present study, we have identified the dihydroorotate dehydrogenase (DHODH), an essential enzyme for the  de novo  biosynthesis of pyrimidine-based nucleotides, to be overexpressed in MCL in comparison to healthy peripheral blood mononuclear cells (PBMC). In vitro inhibition of the DHODH activity using a newly developed DHODH inhibitor, namely ( R )-HZ05, can induce MCL cell death in the nanomolar range independently than the P53 status of the investigated cell lines. Moreover, the combination of ( R )-HZ05 with tyrosine kinase inhibitor shows the synergistic activity on cell death. Pre-clinical investigation on the efficacy of ( R )-HZ05 shows that it can be prolonged animal lifespan similar to ibrutinib. ( R )-HZ05 use in combination with tyrosine kinase inhibitor demonstrated a superior efficacy on tumor burden reduction and survival than either drug alone. We have demonstrated that the depletion of the pyrimidine nucleotide pool, using DHODH inhibitor, represents a new therapeutic strategy that may benefit MCL patients.

【 授权许可】

Unknown