AI Article Synopsis
- Recurrent deletions of tumor suppressor genes often unintentionally remove nearby essential genes, creating a dependence on similar genes called paralogues that might be targeted for cancer treatment.
- The study introduces a new method, called CLIM, to identify these collateral lethal genes, discovering MTHFD2 as a key player in ovarian tumors lacking the UQCR11 gene.
- MTHFD2 supports vital cellular functions by aiding mitochondrial activity, and its inhibition can lead to tumor remission, indicating its potential as a therapeutic target across various cancer types that share UQCR11 deletions.
Article Abstract
Recurrent loss-of-function deletions cause frequent inactivation of tumour suppressor genes but often also involve the collateral deletion of essential genes in chromosomal proximity, engendering dependence on paralogues that maintain similar function. Although these paralogues are attractive anticancer targets, no methodology exists to uncover such collateral lethal genes. Here we report a framework for collateral lethal gene identification via metabolic fluxes, CLIM, and use it to reveal MTHFD2 as a collateral lethal gene in UQCR11-deleted ovarian tumours. We show that MTHFD2 has a non-canonical oxidative function to provide mitochondrial NAD, and demonstrate the regulation of systemic metabolic activity by the paralogue metabolic pathway maintaining metabolic flux compensation. This UQCR11-MTHFD2 collateral lethality is confirmed in vivo, with MTHFD2 inhibition leading to complete remission of UQCR11-deleted ovarian tumours. Using CLIM's machine learning and genome-scale metabolic flux analysis, we elucidate the broad efficacy of targeting MTHFD2 despite distinct cancer genetic profiles co-occurring with UQCR11 deletion and irrespective of stromal compositions of tumours.
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| http://dx.doi.org/10.1038/s42255-022-00636-3 | DOI Listing |
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