DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer

Chao Mao, Xiaoguang Liu, Yilei Zhang, Guang Lei, Yuelong Yan, Hyemin Lee, Pranavi Koppula, Shiqi Wu, Li Zhuang, Bingliang Fang, Masha V. Poyurovsky, Kellen Olszewski () and Boyi Gan ()
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Chao Mao: The University of Texas MD Anderson Cancer Center
Xiaoguang Liu: The University of Texas MD Anderson Cancer Center
Yilei Zhang: The University of Texas MD Anderson Cancer Center
Guang Lei: The University of Texas MD Anderson Cancer Center
Yuelong Yan: The University of Texas MD Anderson Cancer Center
Hyemin Lee: The University of Texas MD Anderson Cancer Center
Pranavi Koppula: The University of Texas MD Anderson Cancer Center
Shiqi Wu: The University of Texas MD Anderson Cancer Center
Li Zhuang: The University of Texas MD Anderson Cancer Center
Bingliang Fang: The University of Texas MD Anderson Cancer Center
Masha V. Poyurovsky: Kadmon Corporation, LLC
Kellen Olszewski: Kadmon Corporation, LLC
Boyi Gan: The University of Texas MD Anderson Cancer Center

Nature, 2021, vol. 593, issue 7860, 586-590

Abstract: Abstract Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1–4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-l-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate—the substrate and product of dihydroorotate dehydrogenase (DHODH)—attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.

Date: 2021
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DOI: 10.1038/s41586-021-03539-7

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