De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases
Patients with brain metastases (BM) face a 90% mortality rate within one year of diagnosis and the current standard of care is palliative. Targeting BM-initiating cells (BMICs) is a feasible strategy to treat BM, but druggable targets are limited. Here, we apply Connectivity Map analysis to lung-, breast-, and melanoma-pre-metastatic BMIC gene expression signatures and identify inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo GTP synthesis pathway, as a target for BM. We show that pharmacological and genetic perturbation of IMPDH attenuates BMIC proliferation in vitro and the formation of BM in vivo. Metabolomic analyses and CRISPR knockout studies confirm that de novo GTP synthesis is a potent metabolic vulnerability in BM. Overall, our work employs a phenotype-guided therapeutic strategy to uncover IMPDH as a relevant target for attenuating BM outgrowth, which may provide an alternative treatment strategy for patients who are otherwise limited to palliation.
Authors
- Chitra Venugopal (ORCID: https://orcid.org/0009-0000-2968-2971)
- Blessing Bassey‐Archibong (ORCID: https://orcid.org/0000-0002-3041-6491)
- Sheila Kumari Singh (ORCID: https://orcid.org/0000-0003-1272-5300)
- Elvin D. de Araujo (ORCID: https://orcid.org/0000-0003-0716-2830)
- Andrew T. Quaile (ORCID: https://orcid.org/0000-0002-1194-3712)
- Agata Kieliszek (ORCID: https://orcid.org/0000-0002-5176-4890)
- Shawn C. Chafe (ORCID: https://orcid.org/0000-0001-8802-651X)
- J. Rafael Montenegro-Burke (ORCID: https://orcid.org/0000-0001-7787-3414)
- Laura Escudero (ORCID: https://orcid.org/0000-0001-7385-673X)
- Muhammad Vaseem Shaikh (ORCID: https://orcid.org/0009-0009-6929-1209)
- Patrick Thomas Gunning (ORCID: https://orcid.org/0000-0003-0654-735X)
- Jarrod W. Johnson (ORCID: https://orcid.org/0000-0002-1214-6862)
- Dillon McKenna (ORCID: https://orcid.org/0009-0000-6803-9786)
- Kui Zhai (ORCID: https://orcid.org/0000-0003-4725-190X)
- William D. Gwynne (ORCID: https://orcid.org/0000-0001-5745-5637)
- Cunjie Zhang (ORCID: https://orcid.org/0000-0003-2257-1923)
- Jakob Magolan (ORCID: https://orcid.org/0000-0002-2947-8580)
- Minomi Subapanditha
- Tomáš Tokár (ORCID: https://orcid.org/0000-0002-4873-0032)
- Daniel Mobilio (ORCID: https://orcid.org/0000-0003-4469-6815)
- Nikoo Aghaei (ORCID: https://orcid.org/0000-0003-3394-668X)
- Abootaleb Sedighi (ORCID: https://orcid.org/0000-0001-5974-1792)
- P T Ang (ORCID: https://orcid.org/0009-0009-1618-9905)
- Mathew L Piotrowski
Institutions
- University Health Network (CA)
- University of Toronto (CA)
- Discovery Centre (CA)
- Krembil Research Institute
- McMaster University (CA)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-10-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101755
- Citations
- 6
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.71
Funders
- McMaster University
- Ontario Institute for Cancer Research
- Canada Foundation for Innovation
- Mitacs
- Canadian Cancer Society Research Institute
- Natural Sciences and Engineering Research Council of Canada
- Science and Engineering Research Council