Abstract
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-driven malignancy, making the viral protein EBNA1 a pivotal therapeutic target. This study evaluates VK-2019, a clinical-stage EBNA1 inhibitor, for its potential to sensitize NPC cells to chemotherapy. We report that VK-2019 synergistically enhances gemcitabine efficacy, reducing the IC50 by nearly 30-fold in EBV-positive C666-1 cells. Transcriptomic profiling combined with in vitro and in vivo models reveals a distinct mechanism: VK-2019 inhibition of EBNA1 downregulates c-MYC, thereby derepressing its downstream target, Proline Dehydrogenase (PRODH). Furthermore, we demonstrate that gemcitabine independently upregulates PRODH via p53 pathway activation. This dual induction of PRODH drives enhanced anti-tumor cytotoxicity. These results provide a prominent preclinical rationale for evaluating VK-2019 in combination regimens and offer a potential therapeutic strategy for patients with EBV-associated nasopharyngeal carcinoma.
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Acknowledgements
H.Y. discloses support for the research of this work from the National Natural Science Foundation of China [grant number 82371123], the Shanghai Science and Technology Committee Foundation [grant number 23Y31900500], the Xuhui Science and Technology Committee Foundation [grant number 25XHYD-24] and the Municipal Hospital Joint Research Project on Emerging and Cutting-edge Technologies of Shanghai Shenkang Hospital Development Center [grant number SHDC12025122]. L.W. discloses support for the research of this work from the National Natural Science Foundation of China [grant number 82301276] and the National Major Science and Technology Project [grant number 2025ZD0544202]. C.L. discloses support for the research of this work from the China Postdoctoral Science Foundation [grant numbers GZC20251389, 2025M772082] and the Natural Science Foundation of Shanghai [grant number 25ZR1402061]. D.G. and Y.L. declare no relevant funding.
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Li, C., Gu, D., Li, Y. et al. VK-2019 enhances gemcitabine’s antitumor activity in EBV-positive nasopharyngeal carcinoma by upregulating PRODH expression. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03247-z
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DOI: https://doi.org/10.1038/s41420-026-03247-z