Clinical-Stage Nanatinostat Triggers Productive Epstein-Barr Virus Lytic Replication

A phase 1b/2 study of the all-oral "kick-and-kill" combo nanatinostat + valganciclovir (nana-val) showed a ~40% overall response rate in patients with relapsed/refractory Epstein-Barr virus (EBV)-associated lymphomas. Despite the promising results in these difficult-to-treat cancers, there is little known about the effects of nanatinostat on EBV and cell death. In this work we demonstrate that nanatinostat, an HDAC1/3 inhibitor, robustly induces the full EBV lytic cycle in a panel of EBV-positive lymphoma and transformed cell lines (Burkitt, DLBCL, lymphoblastoid), spanning viral latency types and EBV genotypes. Nanatinostat drives lytic-gene transcription across all kinetic classes, viral genome replication, and virion release, and kills cells at nanomolar concentrations. Although valganciclovir does not increase cytotoxicity, its ability to block viral DNA synthesis and virion production justifies its inclusion to prevent viral dissemination. Importantly, the two main metabolites of nanatinostat lack histone-H3 acetylation activity and neither activate nor inhibit the EBV lytic phase, indicating that they are biologically inert with respect to EBV. These mechanistic insights clarify the clinical efficacy of nana-val and support further development of kick-and-kill strategies for EBV-driven malignancies.