A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma

Sharmistha Pal; Jakub P. Kaplan; Huy Nguyen; Sylwia A. Stopka; Milan R. Savani; Michael S. Regan; Quang De Nguyen; Kristen L. Jones; Lisa A. Moreau; Jingyu Peng; Marina G. Dipiazza; Andrew J. Perciaccante; Xiaoting Zhu; Bradley R. Hunsel; Kevin X. Liu; Sanda Alexandrescu; Rachid Drissi; Mariella G. Filbin; Samuel K. McBrayer; Nathalie Y.R. Agar; Dipanjan Chowdhury; Daphne A. Haas-Kogan

doi:10.1016/j.ccell.2022.07.012

A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma

Sharmistha Pal, Jakub P. Kaplan, Huy Nguyen, Sylwia A. Stopka, Milan R. Savani, Michael S. Regan, Quang De Nguyen, Kristen L. Jones, Lisa A. Moreau, Jingyu Peng, Marina G. Dipiazza, Andrew J. Perciaccante, Xiaoting Zhu, Bradley R. Hunsel, Kevin X. Liu, Sanda Alexandrescu, Rachid Drissi, Mariella G. Filbin, Samuel K. McBrayer, Nathalie Y.R. AgarDipanjan Chowdhury, Daphne A. Haas-Kogan

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pyrimidine biosynthesis pathway. A clinical stage inhibitor of DHODH (rate-limiting enzyme in the de novo pathway) diminishes uridine-5′-phosphate (UMP) pools, generates DNA damage, and induces apoptosis through suppression of replication forks—an “on-target” effect, as shown by uridine rescue. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.

Original language	English (US)
Pages (from-to)	957-972.e10
Journal	Cancer Cell
Volume	40
Issue number	9
DOIs	https://doi.org/10.1016/j.ccell.2022.07.012
State	Published - Sep 12 2022

Keywords

ATR
BAY2402234
DHODH
DPYD
de novo pyrimidine synthesis
diffuse intrinsic pontine glioma
diffuse midline glioma
elimusertib
pyrimidine degradation
replication stress

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2022.07.012

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Pal, S., Kaplan, J. P., Nguyen, H., Stopka, S. A., Savani, M. R., Regan, M. S., Nguyen, Q. D., Jones, K. L., Moreau, L. A., Peng, J., Dipiazza, M. G., Perciaccante, A. J., Zhu, X., Hunsel, B. R., Liu, K. X., Alexandrescu, S., Drissi, R., Filbin, M. G., McBrayer, S. K., ... Haas-Kogan, D. A. (2022). A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma. Cancer Cell, 40(9), 957-972.e10. https://doi.org/10.1016/j.ccell.2022.07.012

Pal, S, Kaplan, JP, Nguyen, H, Stopka, SA, Savani, MR, Regan, MS, Nguyen, QD, Jones, KL, Moreau, LA, Peng, J, Dipiazza, MG, Perciaccante, AJ, Zhu, X, Hunsel, BR, Liu, KX, Alexandrescu, S, Drissi, R, Filbin, MG, McBrayer, SK, Agar, NYR, Chowdhury, D & Haas-Kogan, DA 2022, 'A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma', Cancer Cell, vol. 40, no. 9, pp. 957-972.e10. https://doi.org/10.1016/j.ccell.2022.07.012

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title = "A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma",

abstract = "Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pyrimidine biosynthesis pathway. A clinical stage inhibitor of DHODH (rate-limiting enzyme in the de novo pathway) diminishes uridine-5′-phosphate (UMP) pools, generates DNA damage, and induces apoptosis through suppression of replication forks—an “on-target” effect, as shown by uridine rescue. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.",

keywords = "ATR, BAY2402234, DHODH, DPYD, de novo pyrimidine synthesis, diffuse intrinsic pontine glioma, diffuse midline glioma, elimusertib, pyrimidine degradation, replication stress",

author = "Sharmistha Pal and Kaplan, {Jakub P.} and Huy Nguyen and Stopka, {Sylwia A.} and Savani, {Milan R.} and Regan, {Michael S.} and Nguyen, {Quang De} and Jones, {Kristen L.} and Moreau, {Lisa A.} and Jingyu Peng and Dipiazza, {Marina G.} and Perciaccante, {Andrew J.} and Xiaoting Zhu and Hunsel, {Bradley R.} and Liu, {Kevin X.} and Sanda Alexandrescu and Rachid Drissi and Filbin, {Mariella G.} and McBrayer, {Samuel K.} and Agar, {Nathalie Y.R.} and Dipanjan Chowdhury and Haas-Kogan, {Daphne A.}",

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AU - Pal, Sharmistha

AU - Kaplan, Jakub P.

AU - Nguyen, Huy

AU - Stopka, Sylwia A.

AU - Savani, Milan R.

AU - Regan, Michael S.

AU - Nguyen, Quang De

AU - Jones, Kristen L.

AU - Moreau, Lisa A.

AU - Peng, Jingyu

AU - Dipiazza, Marina G.

AU - Perciaccante, Andrew J.

AU - Zhu, Xiaoting

AU - Hunsel, Bradley R.

AU - Liu, Kevin X.

AU - Alexandrescu, Sanda

AU - Drissi, Rachid

AU - Filbin, Mariella G.

AU - McBrayer, Samuel K.

AU - Agar, Nathalie Y.R.

AU - Chowdhury, Dipanjan

AU - Haas-Kogan, Daphne A.

PY - 2022/9/12

Y1 - 2022/9/12

N2 - Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pyrimidine biosynthesis pathway. A clinical stage inhibitor of DHODH (rate-limiting enzyme in the de novo pathway) diminishes uridine-5′-phosphate (UMP) pools, generates DNA damage, and induces apoptosis through suppression of replication forks—an “on-target” effect, as shown by uridine rescue. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.

AB - Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pyrimidine biosynthesis pathway. A clinical stage inhibitor of DHODH (rate-limiting enzyme in the de novo pathway) diminishes uridine-5′-phosphate (UMP) pools, generates DNA damage, and induces apoptosis through suppression of replication forks—an “on-target” effect, as shown by uridine rescue. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.

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KW - BAY2402234

KW - DHODH

KW - DPYD

KW - de novo pyrimidine synthesis

KW - diffuse intrinsic pontine glioma

KW - diffuse midline glioma

KW - elimusertib

KW - pyrimidine degradation

KW - replication stress

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DO - 10.1016/j.ccell.2022.07.012

M3 - Article

C2 - 35985342

AN - SCOPUS:85137383052

SN - 1535-6108

VL - 40

SP - 957-972.e10

JO - Cancer Cell

JF - Cancer Cell

IS - 9

ER -

A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma

Abstract

Keywords

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