Nesuparib (JPI-547), a dual tankyrase/PARP inhibitor, exhibits potent antitumor activity in small-cell lung cancer models by modulating Wnt and Hippo signaling pathways

Objectives: Small-cell lung cancer (SCLC) accounts for 13-15% of lung cancers and remains an aggressive malignancy with rapid progression and poor prognosis, as median survival for extensive-stage disease is below 10 months. Nesuparib (JPI-547) is a potent, orally active dual inhibitor of Tankyrase-1/2 (TNKS1/2) and Poly (ADP-ribose) Polymerase-1/2 (PARP1/2). This study evaluated in vitro cytotoxicity and in vivo antitumor efficacy of nesuparib in BRCA wild-type SCLC models. The research aimed to characterize the antitumor activity and mechanism of nesuparib compared with olaparib and irinotecan and assess the synergistic efficacy of nesuparib combined with irinotecan. These investigations sought to clarify the mechanistic and therapeutic potential of dual TNKS1/2-PARP1/2 inhibition in SCLC. Methods: Human SCLC NCI-H146 cells were treated with nesuparib, olaparib, or irinotecan to assess in vitro cytotoxicity by CellTiter-Glo assay. For in vivo evaluation, two independent xenograft studies were performed: a mono-treatment study comparing each agent's antitumor efficacy and a combination study assessing synergistic activity of nesuparib with irinotecan. Tumors from nesuparib-treated mice were analyzed by RT-qPCR, Western blot, and IHC to elucidate molecular mechanisms. Results: In vitro, nesuparib showed the strongest potency among tested agents (IC₅₀ = 2.4 nM), being ~133-fold and ~25-fold more potent than olaparib and irinotecan, respectively. In vivo, nesuparib exhibited a clear dose-dependent tumor-growth inhibition in the NCI-H146 xenograft model. At 50 mg/kg, nesuparib achieved a TGI of 65.4%, exceeding the efficacy of olaparib (36.0%) and irinotecan 10 mg/kg (42.9%). Combination with irinotecan produced a significant synergistic effect, resulting in enhanced and sustained tumor regression, which was superior to the combination of olaparib with irinotecan. Mechanistic analyses revealed that nesuparib suppressed Wnt and Hippo signaling pathways, leading to inhibition of tumor growth, as confirmed by qPCR, Western blot, and IHC. Conclusions: Nesuparib (JPI-547), a dual TNKS1/2-PARP1/2 inhibitor, showed strong dose-dependent antitumor activity in BRCA wild-type SCLC. Combination with irinotecan produced a synergistic tumor-suppressive effect. Mechanistic studies indicated that nesuparib inhibited tumor growth by suppressing Wnt and Hippo signaling, supporting its potential as a novel therapeutic strategy for SCLC alone or with DNA-damaging agents.