Abstract
Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 939-956.e16 |
| Journal | Cancer Cell |
| Volume | 40 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 12 2022 |
Keywords
- DHODH
- IDH
- cancer metabolism
- genetically engineered mouse model
- glioma
- isocitrate dehydrogenase
- pyrimidine nucleotides
ASJC Scopus subject areas
- Oncology
- Cancer Research
Fingerprint
Dive into the research topics of 'De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
In: Cancer Cell, Vol. 40, No. 9, 12.09.2022, p. 939-956.e16.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma
AU - Shi, Diana D.
AU - Savani, Milan R.
AU - Levitt, Michael M.
AU - Wang, Adam C.
AU - Endress, Jennifer E.
AU - Bird, Cylaina E.
AU - Buehler, Joseph
AU - Stopka, Sylwia A.
AU - Regan, Michael S.
AU - Lin, Yu Fen
AU - Puliyappadamba, Vinesh T.
AU - Gao, Wenhua
AU - Khanal, Januka
AU - Evans, Laura
AU - Lee, Joyce H.
AU - Guo, Lei
AU - Xiao, Yi
AU - Xu, Min
AU - Huang, Bofu
AU - Jennings, Rebecca B.
AU - Bonal, Dennis M.
AU - Martin-Sandoval, Misty S.
AU - Dang, Tammie
AU - Gattie, Lauren C.
AU - Cameron, Amy B.
AU - Lee, Sungwoo
AU - Asara, John M.
AU - Kornblum, Harley I.
AU - Mak, Tak W.
AU - Looper, Ryan E.
AU - Nguyen, Quang De
AU - Signoretti, Sabina
AU - Gradl, Stefan
AU - Sutter, Andreas
AU - Jeffers, Michael
AU - Janzer, Andreas
AU - Lehrman, Mark A.
AU - Zacharias, Lauren G.
AU - Mathews, Thomas P.
AU - Losman, Julie Aurore
AU - Richardson, Timothy E.
AU - Cahill, Daniel P.
AU - DeBerardinis, Ralph J.
AU - Ligon, Keith L.
AU - Xu, Lin
AU - Ly, Peter
AU - Agar, Nathalie Y.R.
AU - Abdullah, Kalil G.
AU - Harris, Isaac S.
AU - Kaelin, William G.
AU - McBrayer, Samuel K.
N1 - Funding Information: The authors thank C. Stiles (DFCI), T. Batchelor (BWH), and S. Morrison (UTSW) for insightful feedback; J. Alberta (DFCI) for sharing Olig2 antibody; J. Brugge (HMS) for supporting development of the MAPS platform; Kaelin, McBrayer, Abdullah, DeBerardinis, and Losman laboratory members for helpful discussions; I. Mellinghoff (MSKCC), S. Weiss (Univ. of Calgary), and R. Pieper (UCSF) for sharing cell lines; Bayer Pharmaceuticals for sharing BAY 2402234; M. Yuan (Harvard) for help with mass spectrometry; M. Phillips (UTSW) for guidance on measuring DHODH activity; and DFCI Animal Resources Facility and UTSW Animal Resource Center for help with mouse work. This study was supported by awards from the Broad-Bayer Alliance (Joint Project Proposal Grant 7000062-5500001463 ) and from NIH / NCI : K22CA237752 to S.K.M., R01CA258586 to S.K.M. and K.G.A., P50CA165962 to N.Y.R.A, D.P.C., K.L.L., and W.G.K. (and related Career Enhancement Project award to S.K.M.), U19CA264504 to N.Y.R.A, D.P.C., K.L.L., W.G.K., and S.K.M., P50CA211015 to H.I.K., 5R35CA210068-02 to W.G.K, F30CA271634 to M.R.S., U54CA210180 to N.Y.R.A, P41EB028741 to N.Y.R.A, R35CA22044901 to R.J.D., and T32EB025823 to S.A.S. N.Y.R.A. is supported by the Pediatric Low-Grade Astrocytoma Program at PBTF . Drug screening using MAPS by J.E.E. and I.S.H. was supported by the Ludwig Center at Harvard and ICCB-L . Organoid modeling work was partly supported by an award from Oligo Nation Foundation to S.K.M. and K.G.A. S.K.M. is supported by a Cancer Prevention and Research Institute of Texas (CPRIT) award ( RR190034 ), a V Scholar Award from the V Foundation for Cancer Research ( V2020-006 ), a Distinguished Scientist Award from the Sontag Foundation , a Moody Medical Research Institute award, and a gift from the Jonesville Foundation . D.D.S. was supported by the HHMI Medical Research Fellows Program, the Scholars in Medicine Program at Harvard Medical School , a Conquer Cancer Young Investigator Award, and the ASTRO Resident Research Biology Seed Grant. W.G.K. and R.J.D. are HHMI Investigators. K.G.A. is supported by the Eugene P. Frenkel, MD, Endowment. C.E.B. is supported by an award from the Burroughs Wellcome Trust . Funding Information: R.J.D., W.G.K., and S.K.M. have served as paid advisors to Agios Pharmaceuticals. W.G.K. receives compensation for roles as an Eli Lilly and LifeMine Therapeutics Board Director, a founder of Tango Therapeutics and Cedilla Therapeutics, and a scientific advisor for Fibrogen, IconOVir Bio, Circle Pharma, Nextext Invest, and Casdin Capital. K.L.L. receives research support from Eli Lilly and Company via the DFCI. S.K.M. and W.G.K. received research funding from Bayer Pharmaceuticals. Bayer had no influence over the design, execution, or interpretation of studies. N.Y.R.A. is key opinion leader for Bruker Daltonics, scientific advisor to Invicro, and receives support from Thermo Finnegan and EMD Serono. S.G., A.S., M.S., A.J., and L.E. are employees at Bayer. S.G., A.S., and A.J. hold stock in Bayer. D.P.C. has consulted for Lilly, GlaxoSmithKline, and Boston Pharmaceuticals and serves on the advisory board of Pyramid Biosciences, which includes an equity interest. All other authors declare no competing interests. Funding Information: The authors thank C. Stiles (DFCI), T. Batchelor (BWH), and S. Morrison (UTSW) for insightful feedback; J. Alberta (DFCI) for sharing Olig2 antibody; J. Brugge (HMS) for supporting development of the MAPS platform; Kaelin, McBrayer, Abdullah, DeBerardinis, and Losman laboratory members for helpful discussions; I. Mellinghoff (MSKCC), S. Weiss (Univ. of Calgary), and R. Pieper (UCSF) for sharing cell lines; Bayer Pharmaceuticals for sharing BAY 2402234; M. Yuan (Harvard) for help with mass spectrometry; M. Phillips (UTSW) for guidance on measuring DHODH activity; and DFCI Animal Resources Facility and UTSW Animal Resource Center for help with mouse work. This study was supported by awards from the Broad-Bayer Alliance (Joint Project Proposal Grant 7000062-5500001463) and from NIH/NCI: K22CA237752 to S.K.M. R01CA258586 to S.K.M. and K.G.A. P50CA165962 to N.Y.R.A, D.P.C. K.L.L. and W.G.K. (and related Career Enhancement Project award to S.K.M.), U19CA264504 to N.Y.R.A, D.P.C. K.L.L. W.G.K. and S.K.M. P50CA211015 to H.I.K. 5R35CA210068-02 to W.G.K, F30CA271634 to M.R.S. U54CA210180 to N.Y.R.A, P41EB028741 to N.Y.R.A, R35CA22044901 to R.J.D. and T32EB025823 to S.A.S. N.Y.R.A. is supported by the Pediatric Low-Grade Astrocytoma Program at PBTF. Drug screening using MAPS by J.E.E. and I.S.H. was supported by the Ludwig Center at Harvard and ICCB-L. Organoid modeling work was partly supported by an award from Oligo Nation Foundation to S.K.M. and K.G.A. S.K.M. is supported by a Cancer Prevention and Research Institute of Texas (CPRIT) award (RR190034), a V Scholar Award from the V Foundation for Cancer Research (V2020-006), a Distinguished Scientist Award from the Sontag Foundation, a Moody Medical Research Institute award, and a gift from the Jonesville Foundation. D.D.S. was supported by the HHMI Medical Research Fellows Program, the Scholars in Medicine Program at Harvard Medical School, a Conquer Cancer Young Investigator Award, and the ASTRO Resident Research Biology Seed Grant. W.G.K. and R.J.D. are HHMI Investigators. K.G.A. is supported by the Eugene P. Frenkel, MD, Endowment. C.E.B. is supported by an award from the Burroughs Wellcome Trust. D.D.S. and S.K.M. did the experiments and, with K.G.A. and W.G.K. designed the experiments, analyzed data, and wrote the manuscript. M.R.S. and M.M.L. did stable isotope tracing and metabolomics experiments. M.R.S. and L.G. performed bioinformatics analysis with guidance from L.X. L.E. and J.-A.L. developed the drug-resistant DHODH mutant. A.C.W. W.G. and J.K. helped to create the astrocytoma GEM model. J.E.E. and I.S.H. developed and used the MAPS platform. C.E.B. and J.B. established and treated organoid models and L.C.G. managed related clinical data. S.A.S. and M.S.R. performed MALDI-MSI experiments and interpreted the data with N.Y.R.A. Y.-F.L. and M.X. performed DNA damage assays and analyzed data with P.L. B.H. and S.L. helped to genetically engineer NHA cells and evaluated their transformation status. R.B.J. did immunohistochemistry and analyzed results with S.S. Y.X. helped to perform experiments using GSC lines. V.T.P. performed surgeries to generate orthotopic xenograft mouse models. D.B. performed MRI studies and interpreted data with Q.-D.N. A.B.C. performed in vivo dosing and bioluminescence imaging and interpreted data with Q.-D.N. M.S.M.-S. J.M.A. L.G.Z. J.H.L. and T.P.M. conducted and/or analyzed LC-MS studies. R.E.L. synthesized (R)-2HG-TFMB. T.D. quantified N-linked glycans and, with M.A.L. interpreted data. H.I.K. T.W.M. D.P.C. and K.L.L. provided GSC and/or mouse models and guidance on their use. S.G. A.S. M.J. and A.J. provided BAY 2402234 and guidance on its use in preclinical models. K.L.L. and T.E.R. performed neuropathology evaluations of tissues from our GEM and organoid models, respectively. D.P.C. R.J.D. and K.L.L. helped to design and interpret experiments. R.J.D. W.G.K. and S.K.M. have served as paid advisors to Agios Pharmaceuticals. W.G.K. receives compensation for roles as an Eli Lilly and LifeMine Therapeutics Board Director, a founder of Tango Therapeutics and Cedilla Therapeutics, and a scientific advisor for Fibrogen, IconOVir Bio, Circle Pharma, Nextext Invest, and Casdin Capital. K.L.L. receives research support from Eli Lilly and Company via the DFCI. S.K.M. and W.G.K. received research funding from Bayer Pharmaceuticals. Bayer had no influence over the design, execution, or interpretation of studies. N.Y.R.A. is key opinion leader for Bruker Daltonics, scientific advisor to Invicro, and receives support from Thermo Finnegan and EMD Serono. S.G. A.S. M.S. A.J. and L.E. are employees at Bayer. S.G. A.S. and A.J. hold stock in Bayer. D.P.C. has consulted for Lilly, GlaxoSmithKline, and Boston Pharmaceuticals and serves on the advisory board of Pyramid Biosciences, which includes an equity interest. All other authors declare no competing interests. Publisher Copyright: © 2022 The Author(s)
PY - 2022/9/12
Y1 - 2022/9/12
N2 - Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.
AB - Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.
KW - DHODH
KW - IDH
KW - cancer metabolism
KW - genetically engineered mouse model
KW - glioma
KW - isocitrate dehydrogenase
KW - pyrimidine nucleotides
UR - http://www.scopus.com/inward/record.url?scp=85137396017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85137396017&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2022.07.011
DO - 10.1016/j.ccell.2022.07.011
M3 - Article
C2 - 35985343
AN - SCOPUS:85137396017
SN - 1535-6108
VL - 40
SP - 939-956.e16
JO - Cancer Cell
JF - Cancer Cell
IS - 9
ER -