VK-2019 enhances gemcitabine’s antitumor activity in EBV-positive nasopharyngeal carcinoma by upregulating PRODH expression

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.