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Impact of small molecule‐mediated inhibition of ammonia detoxification on lung malignancies and liver metabolism


Makris, Georgios; Kayhan, Semih; Kreuzer, Marvin; Rüfenacht, Véronique; Faccin, Erica; Underhaug, Jarl; Diez‐Fernandez, Carmen; Knobel, Philip A; Poms, Martin; Gougeard, Nadine; Rubio, Vicente; Martinez, Aurora; Pruschy, Martin; Häberle, Johannes (2023). Impact of small molecule‐mediated inhibition of ammonia detoxification on lung malignancies and liver metabolism. Cancer Communications, 43(4):508-512.

Abstract

Metabolically induced cancer heterogeneity creates a largesourceofnovelpotentialtargetstowardsanenhancedther-apeutic window alone and in combination with classicchemo-andradiotherapy[1,2 ].Thisisofparticularinterestfor non-small cell lung cancer (NSCLC), which accountsfor more than 80% of all lung tumor types characterizedby limited responses to current treatment options [3–5].Genetically-definedKRAS/LKB1-mutant NSCLC tumorsexploit the proximal urea cycle enzyme carbamoyl phos-phate synthetase 1 (CPS1) as an intermediate step forpyrimidine biosynthesis, thereby contrasting its crucialhepatic role in ammonia detoxification [6–8]. Thus, CPS1could serve as a novel target for NSCLC susceptibility(Figure1A). In this study, we investigated the metabolicchanges observed in both NSCLC and healthy hepaticsystems following the identification, characterization andapplication of a small molecule inhibitor of ectopic CPS1functionality.

Abstract

Metabolically induced cancer heterogeneity creates a largesourceofnovelpotentialtargetstowardsanenhancedther-apeutic window alone and in combination with classicchemo-andradiotherapy[1,2 ].Thisisofparticularinterestfor non-small cell lung cancer (NSCLC), which accountsfor more than 80% of all lung tumor types characterizedby limited responses to current treatment options [3–5].Genetically-definedKRAS/LKB1-mutant NSCLC tumorsexploit the proximal urea cycle enzyme carbamoyl phos-phate synthetase 1 (CPS1) as an intermediate step forpyrimidine biosynthesis, thereby contrasting its crucialhepatic role in ammonia detoxification [6–8]. Thus, CPS1could serve as a novel target for NSCLC susceptibility(Figure1A). In this study, we investigated the metabolicchanges observed in both NSCLC and healthy hepaticsystems following the identification, characterization andapplication of a small molecule inhibitor of ectopic CPS1functionality.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > University Hospital Zurich > Clinic for Radiation Oncology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Cancer Research, Oncology
Language:English
Date:April 2023
Deposited On:30 Jan 2023 10:35
Last Modified:29 Mar 2024 02:39
Publisher:Wiley Open Access
ISSN:2523-3548
Additional Information:LETTER TO THE EDITOR
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/cac2.12402
PubMed ID:36708276
  • Content: Published Version
  • Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)