Cellular Responses Induced by NCT-503 Treatment on Triple-Negative Breast Cancer Cell Lines - A Proteomics Approach

Sep 21, 2026

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Breast cancer remains a major cause of mortality, and triple-negative breast cancer (TNBC) is notable for aggressive behavior and limited treatment options. By focusing on metabolic reprogramming, this study evaluated de novo serine biosynthetic pathway inhibition through NCT-503, specifically targeting phosphoglycerate dehydrogenase (PHGDH). Using MS-based proteomics, cytotoxicity testing, and label-free bottom-up proteomics, the work characterized intracellular and secreted proteome changes across MDA-MB-231, MDA-MB-468, and Hs 578T.

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biomedicines Article Cellular Responses Induced by NCT-503 Treatment on Triple-Negative Breast Cancer Cell Lines: A Proteomics Approach Ioana-Ecaterina Pralea 1,2, Radu-Cristian Moldovan 1, Adrian-Bogdan T, igu 3, Cristian-Silviu Moldovan 4, Eva Fischer-Fodor 5 and Cristina-Adela Iuga 1,2, * Citation: Pralea, I.-E.; Moldovan, R.-C.; T, igu, A.-B.; Moldovan, C.-S.; Fischer-Fodor, E.; Iuga, C.-A. Cellular Responses Induced by NCT-503 Treatment on Triple-Negative Breast Cancer Cell Lines: A Proteomics Approach. Biomedicines 2024, 12, 1087 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)biomedicines12051087 Academic Editors: Matteo Lazzeroni and Sushma Yadav Received: 21 March 2024 Revised: 26 April 2024 Accepted: 10 May 2024 Published: 14 May 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Proteomics and Metabolomics, Research Center for Advanced Medicine–MedFuture,“Iuliu Hat, ieganu” University of Medicine and Pharmacy Cluj-Napoca, Louis Pasteur Street 4-6, 400349 Cluj-Napoca, Romania; [pralea.ioana@umfcluj.ro](pralea.ioana@umfcluj.ro) (I.-E.P.); [moldovan.radu@umfcluj.ro](moldovan.radu@umfcluj.ro) (R.-C.M.) 2 Department of Pharmaceutical Analysis, Faculty of Pharmacy,“Iuliu Haieganu” University of Medicine and Pharmacy, Louis Pasteur Street 6, 400349 Cluj-Napoca, Romania 3 Department of Translational Medicine, Research Center for Advanced Medicine–MedFuture,“Iuliu Hat, ieganu” University of Medicine and Pharmacy Cluj-Napoca, Louis Pasteur Street 6, 400349 Cluj-Napoca, Romania; [bogdan.tigu@umfcluj.ro](bogdan.tigu@umfcluj.ro) 4 Department of BioNanoPhysics, Research Center for Advanced Medicine–MedFuture,“Iuliu Haieganu” University of Medicine and Pharmacy Cluj-Napoca, Louis Pasteur Street 6, 400349 Cluj-Napoca, Romania; [moldovan.cristian1994@gmail.com](moldovan.cristian1994@gmail.com) 5 Tumor Biology Department, Institute of Oncology “Prof. Dr. Ion Chiricut, ă”, 400015 Cluj-Napoca, Romania; [fischer.eva@iocn.ro](fischer.eva@iocn.ro) * Correspondence: [iugac@umfcluj.ro](iugac@umfcluj.ro) Abstract: Breast cancer (BC) remains one of the leading causes of mortality among women, with triplenegative breast cancer (TNBC) standing out for its aggressive nature and limited treatment options. Metabolic reprogramming, one of cancer’s hallmarks, underscores the importance of targeting metabolic vulnerabilities for therapeutic intervention. This study aimed to investigate the impact of de novo serine biosynthetic pathway (SSP) inhibition, specifically targeting phosphoglycerate dehydrogenase (PHGDH) with NCT-503, on three TNBC cell lines: MDA-MB-231, MDA-MB-468 and Hs 578T. First, MS-based proteomics was used to confirm the distinct expression of PHGDHand other SSP enzymes using the intracellular proteome profiles of untreated cells. Furthermore, to characterize the response of the TNBC cell lines to the inhibitor, both in vitro assays and label-free, bottom-up proteomics were employed. NCT-503 exhibited significant cytotoxic effects on all three cell lines, with MDA-MB-468 being the most susceptible (IC 50 20.2 ± 2.8 µM), while MDA-MB-231 and Hs 578T showed higher, comparable IC 50s. Notably, differentially expressed proteins (DEPs) induced by NCT-503 treatment were mostly cell line-specific, both in terms of the intracellular and secreted proteins. Through overrepresentation and Reactome GSEA analysis, modifications of the intracellular proteins associated with cell cycle pathways were observed in the MDA-MBs following treatment. Distinctive dysregulation of signaling pathways were seen in all TNBC cell lines, while modifications of prot

FAQs

What is the main therapeutic target evaluated in this study?

The study targets the de novo serine biosynthetic pathway by inhibiting phosphoglycerate dehydrogenase (PHGDH) using NCT-503.

Which TNBC cell lines were used to assess the effects of NCT-503?

The experiments were performed on three TNBC cell lines: MDA-MB-231, MDA-MB-468, and Hs 578T.

What types of proteomics analyses were performed?

The authors used MS-based proteomics to confirm enzyme expression and label-free bottom-up proteomics to characterize treatment-induced intracellular and secreted protein responses.

Sep 21, 2026

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