PO.ET06.02 · 实验与分子治疗

Nesuparib（JPI-547）作为一种 tankyrase/PARP 双重抑制剂，通过调节 Wnt 和 Hippo 信号通路在小细胞肺癌模型中展现出强效抗肿瘤活性

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

编号 248 展板 19 时间 4/19 02:00–05:00 区域 Section 11 主讲 Jun Kim

分会场 DNA Damage and Repair 1

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作者与单位 Authors & Affiliations

Jun Kim¹, Joon-Hyung Lee¹, John Kim¹, Hyunju Cha¹, Seounghun Kang²

¹Onconic Therapeutics, Seoul, Korea, Republic of,²Soongsil University, Seoul, Korea, Republic of

摘要 Abstract

中文摘要

目的：小细胞肺癌（SCLC）占肺癌的 13-15%，仍是一种进展迅速、预后不良的侵袭性恶性肿瘤，广泛期疾病的中位生存期低于 10 个月。Nesuparib（JPI-547）是一种强效、口服活性的 Tankyrase-1/2（TNKS1/2）和聚（ADP-核糖）聚合酶-1/2（PARP1/2）双重抑制剂。本研究评估了 nesuparib 在 BRCA 野生型 SCLC 模型中的体外细胞毒性和体内抗肿瘤疗效。研究旨在表征 nesuparib 与 olaparib 和 irinotecan 相比的抗肿瘤活性和机制，并评估 nesuparib 联合 irinotecan 的协同疗效。这些研究旨在阐明 TNKS1/2-PARP1/2 双重抑制在 SCLC 中的机制和治疗潜力。方法：用 nesuparib、olaparib 或 irinotecan 处理人 SCLC NCI-H146 细胞，通过 CellTiter-Glo 检测评估体外细胞毒性。在体内评估方面，进行了两项独立的异种移植研究：一项比较各药物抗肿瘤疗效的单药治疗研究，以及一项评估 nesuparib 与 irinotecan 协同活性的联合研究。对 nesuparib 处理小鼠的肿瘤进行 RT-qPCR、Western blot 和 IHC 分析，以阐明分子机制。结果：在体外，nesuparib 在受试药物中显示最强效力（IC₅₀ = 2.4 nM），分别比 olaparib 和 irinotecan 强约 133 倍和约 25 倍。在体内，nesuparib 在 NCI-H146 异种移植模型中表现出明显的剂量依赖性肿瘤生长抑制。在 50 mg/kg 剂量下，nesuparib 实现了 65.4% 的 TGI，超过了 olaparib（36.0%）和 irinotecan 10 mg/kg（42.9%）的疗效。与 irinotecan 联合产生了显著的协同效应，导致肿瘤消退增强且持久，优于 olaparib 与 irinotecan 的联合。机制分析显示 nesuparib 抑制 Wnt 和 Hippo 信号通路，从而抑制肿瘤生长，这已由 qPCR、Western blot 和 IHC 证实。结论：Nesuparib（JPI-547）作为一种 TNKS1/2-PARP1/2 双重抑制剂，在 BRCA 野生型 SCLC 中显示出强效的剂量依赖性抗肿瘤活性。与 irinotecan 联合产生协同性肿瘤抑制效应。机制研究表明 nesuparib 通过抑制 Wnt 和 Hippo 信号来抑制肿瘤生长，支持其作为 SCLC 单药或与 DNA 损伤剂联合的新型治疗策略的潜力。

查看英文原文 English abstract

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.

利益披露 Disclosure

J. Kim, Onconic therapeutics Employment, ). J. Lee, onconic therapeutics Employment. J. Kim, Onconic therapeutics Employment, g., Board of Directors, non-salaried role). H. Cha, Onconic therapeutics Employment.

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