Tumor-versus-nonmalignant quantitative drug sensitivity profiling identifies capivasertib as a selective therapeutic...

Nasopharyngeal carcinoma (NPC) remains a therapeutic challenge, particularly in the recurrent or treatment-refractory setting, underscoring the need for tumor-selective therapeutic strategies. In this study, we applied a tumor-normal-paired high-throughput drug sensitivity screening approach using two biologically distinct NPC cell lines, EBV-positive C666-1 and EBV-negative CNE2, together with normal nasopharyngeal epithelial cells as a normal control. This design enabled direct identification of compounds with selective anti-NPC activity while sparing normal counterpart. Drug sensitivity profiling identified several agents with established clinical relevance in NPC, validating the screening strategy. Among novel candidates, the AKT inhibitor capivasertib emerged as a highly selective inhibitor of NPC cell viability, with IC₅₀ values in the nanomolar to low micromolar range. Capivasertib demonstrated synergistic activity with platinum-based chemotherapy and enhanced radiosensitivity in NPC cells. In vivo, capivasertib significantly suppressed tumor growth and its combination with cisplatin significantly prolonged survival in xenograft models without inducing overt systemic toxicity. Mechanistically, capivasertib treatment increased AKT phosphorylation, consistent with pharmacodynamic target engagement, while suppressing downstream mTOR/4EBP1 signaling and inducing pro-apoptotic levels. Collectively, these findings demonstrate that Akt/mTOR inhibition by capivasertib enhances therapeutic efficacy in preclinical NPC models and provides rationale for further clinical evaluation of capivasertib in advanced NPC.