De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases

• Published in: Cell reports. Medicine 2024-10, Vol.5 (10), p.101755, Article 101755
• Main Authors: Kieliszek, Agata M., Mobilio, Daniel, Bassey-Archibong, Blessing I., Johnson, Jarrod W., Piotrowski, Mathew L., de Araujo, Elvin D., Sedighi, Abootaleb, Aghaei, Nikoo, Escudero, Laura, Ang, Patrick, Gwynne, William D., Zhang, Cunjie, Quaile, Andrew, McKenna, Dillon, Subapanditha, Minomi, Tokar, Tomas, Vaseem Shaikh, Muhammad, Zhai, Kui, Chafe, Shawn C., Gunning, Patrick T., Montenegro-Burke, J. Rafael, Venugopal, Chitra, Magolan, Jakob, Singh, Sheila K.
• Format: Article
• Language: English
• Subjects: Animals; brain metastases; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - secondary; cancer stem cells; Cell Line, Tumor; Cell Proliferation; Female; GTP synthesis; Guanosine Triphosphate - metabolism; Humans; IMP Dehydrogenase - genetics; IMP Dehydrogenase - metabolism; IMPDH; Mice
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101755

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. [Display omitted] •Connectivity Map analysis performed on a pre-metastatic transcriptomic signature•Drug discovery via phenotypic screen identifies mycophenolic acid•Targeting IMPDH with mycophenolic acid slows brain metastasis formation•IMPDH is a potential biomarker for at-risk patients with lung cancer Kieliszek et al. use a phenotypic drug discovery approach to identify IMPDH as a targetable metabolic vulnerability in brain metastasis. Medicinal chemistry efforts suggest that prioritizing the BBB permeability of IMPDH inhibitors enhances their preclinical efficacy. Targeting IMPDH represents an avenue to block brain metastasis formation in at-risk patients with cancer.