PO.ET09.06 · 实验与分子治疗
发现 JMKX005425——一种在多种 MSI-H 胃癌模型中高效的强效 WRN 抑制剂
Discovery of JMKX005425, a potent WRN inhibitor highly efficacious in multiple MSI-H gastric cancer models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
Werner 综合征解旋酶（WRN）在 DNA 修复和基因组完整性维持中发挥重要作用。近期研究已验证 WRN 是微卫星高度不稳定（MSI-H）肿瘤一个有前景的合成致死靶点，这类肿瘤在结直肠癌（CRC）、胃癌（GC）和子宫内膜癌（EC）中患病率最高。虽然 WRN 抑制剂作为单药在 MSI-H CRC 中已显示出有前景的疗效，但其在 MSI-H GC 中的治疗潜力仍有待进一步评估。JMKX005425 是由捷友（JeYou）开发的一种处于临床阶段的口服 WRN 抑制剂，用于治疗 MSI-H 癌症。JMKX005425 强效抑制 WRN 活性，并对多种 MSI-H 的 CRC、GC 和 EC 细胞表现出选择性的抗增殖作用，而对微卫星稳定的癌细胞则无此作用。JMKX005425 还在 MSI-H 细胞中引起 DNA 损伤反应，表现为 gammaH2AX 诱导和 WRN 降解。在体内，JMKX005425 单药在多种 MSI-H 细胞系来源异种移植（CDX）和患者来源异种移植（PDX）模型中高度有效，包括来自经过多线治疗、免疫治疗难治患者的模型。值得注意的是，在一组 MSI-H GC PDX（n=14）中，每日口服 JMKX005425 治疗 4 周后，超过 50% 的模型出现了显著的肿瘤消退，定义为肿瘤生长抑制（TGI）超过 100%，且除两个模型外所有模型的 TGI 均超过 65%（范围：68.2% 至 118.8%）。此外，低剂量 JMKX005425 联合伊立替康在一个 MSI-H CDX 模型中完全抑制了肿瘤生长。最后，在 MSI-H 细胞中进行的全基因组 CRISPR 筛选鉴定出若干对 JMKX005425 治疗敏感性的调节因子，可为进一步研究耐药或患者选择提供信息。总之，JMKX005425 是一种强效、选择性的 WRN 抑制剂，在多种 MSI-H 模型（尤其是 GC PDX 模型）中显示出高效活性，凸显了其作为 MSI-H 胃癌有前景疗法的潜力。JMKX005425 目前正在中国开展一项针对晚期 MSI-H/dMMR 实体瘤患者的 I 期剂量递增研究（CTR20253477）。
查看英文原文 English abstract
The Werner Syndrome Helicase (WRN) plays an important role in DNA repair and the maintenance of genome integrity. Recent studies have validated WRN as a promising synthetic lethal target for microsatellite instability-high (MSI-H) tumors, which have the highest prevalence in colorectal (CRC), gastric (GC) and endometrial cancers (EC). While WRN inhibitors as monotherapy in MSI-H CRC have showed promising efficacy, their therapeutic potential in MSI-H GC needs to be further evaluated. JMKX005425 is a clinical-stage, oral WRN inhibitor developed by JeYou to treat MSI-H cancers. JMKX005425 potently inhibited WRN activity and showed selective anti-proliferative effects against various MSI-H CRC, GC and EC cells but not microsatellite stable cancer cells. JMKX005425 also caused DNA damage response as measured by gammaH2AX induction and WRN degradation in MSI-H cells. In vivo, JMKX005425 monotherapy was highly efficacious in multiple MSI-H Cell Line-Derived Xenografts (CDX) and Patient-Derived Xenografts (PDX) models, including those from heavily-treated, immunotherapy-refractory patients. Notably, in a panel of MSI-H GC PDX (n=14), daily oral administration of JMKX005425 led to significant tumor regression, defined as tumor growth inhibition (TGI) over 100%, in over 50% of the models after 4 weeks of treatment, and all but two of the models showed a TGI over 65% (range: 68.2% to 118.8%). Furthermore, low dose of JMKX005425 in combination with irinotecan completed suppressed tumor growth in an MSI-H CDX model. Last, whole-genome CRISPR screens in MSI-H cells identified several modifiers of sensitivity to JMKX005425 treatment, which may provide information for further studies of drug resistance or patient selection. In conclusion, JMKX005425 is a potent, selective WRN inhibitor and shows high efficacy in multiple MSI-H models, especially in GC PDX models, highlighting its potential as a promising treatment for MSI-H gastric cancer. JMKX005425 is current in a phase I dose escalation study in patients with advanced MSI-H/dMMR solid tumors in China (CTR20253477).
利益披露 Disclosure
L. Yue, None..
X. Lin, None..
X. Liu, None..
Y. Qiu, None..
S. Yang, None..
D. Li, None..
W. Chen, None..
T. B. Guo, None..
J. Peng, None.