DHODH as a targetable metabolic Achilles’ heel for chemotherapy-resistant B-ALL
Abstract
Abstract Relapse remains a major barrier to survival in B-cell acute lymphoblastic leukemia (B-ALL). Both activation of B-cell signaling pathways and increased glucose consumption have been linked to chemoresistance and relapse risk. In this study, we connect these observations by showing that B-ALL cells with active mTOR signaling, marked by high phosphorylated ribosomal protein S6 (pS6+), are glucose dependent. Isotope tracing confirms that pS6+ cells are highly glycolytic and rely on glucose for de novo nucleotide synthesis. Uridine, but not other purines or pyrimidines, rescue pS6+ cells from glucose deprivation, highlighting uridine as essential for survival. Active mammalian target of rapamycin (mTOR) signaling in pS6+ cells drives de novo pyrimidine synthesis by activating carbamoyl phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the initial steps of de novo pyrimidine synthesis. Inhibiting signaling abolishes glucose dependency and CAD phosphorylation. Primary pS6+ cells express high levels of pyrimidine synthesis proteins, including dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in pyrimidine synthesis. Increased DHODH expression correlates with relapse and poor event-free survival. Most B-ALL molecular subtypes exhibit DHODH activity. BAY-2402234, a DHODH inhibitor, effectively kills pS6+ cells in vitro, with 50% inhibitory concentration values correlating with pS6 signaling strength across 14 xenografts derived from patients with B-ALL. In vivo, DHODH inhibition prolongs survival and reduces leukemia burden in pS6+ B-ALL models. Together, these findings link active signaling to pyrimidine dependency and relapse risk, highlighting DHODH inhibition as a promising therapeutic strategy for chemotherapy-resistant B-ALL.
Article Details
Authors (30)
Yuxuan Liu
Haowen Jiang
Department of Radiation Oncology, Stanford University
Jingjing Liu
Lucille Stuani
Milton Merchant
Astraea Jager
Abhishek Koladiya
1Division of Hematology, Oncology, and Stem Cell Transplantation & Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA
Ti-Cheng Chang
Pablo Domizi
Jolanda Sarno
Ao Wang
Timothy Keyes
Dorra Jedoui
1Division of Hematology, Oncology, and Stem Cell Transplantation & Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA
Jodie Meng
1Division of Hematology, Oncology, and Stem Cell Transplantation & Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA
Felix J. Hartmann
Ruida Hou
9Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
Carol Fries
10Pediatric Hematology/Oncology Division, Department of Pediatrics, University of Rochester, Rochester, NY
Chiara Pirillo
1Division of Hematology, Oncology, and Stem Cell Transplantation & Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA
Qingsong Gao
2Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Ilaria Iacobucci
2Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Sean C. Bendall
Min Huang
Norman J. Lacayo
1Division of Hematology, Oncology, and Stem Cell Transplantation & Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA
Kathleen M. Sakamoto
Charles G. Mullighan
Mignon Loh
13Ben Towne Center for Childhood Cancer Research and the Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA
Jiyang Yu
Department of Chemistry, Advanced Institute of Future Energy, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, State Key Laboratory of Porous Materials for Separation and Conversion
Jun J. Yang
Department of Pharmacy and Pharmaceutical Sciences
Jiangbin Ye
Department of Radiation Oncology, Stanford University
Kara L. Davis