Cell reports. Medicine · 2024
De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.