中国病理生理杂志2026，Vol.42Issue(3)：417-427,11.DOI:10.3969/j.issn.1000-4718.2026.03.001
MRTX1133联合SMAD3抑制剂作用于KRAS G12D突变胰腺癌细胞的机制研究
Effects of MRTX1133 combined with SMAD3 inhibitor on pancreatic carcinoma cells with KRAS G12D mutation and their mechanism
摘要
Abstract
AIM:To investigate the combining effect of a specific Kirsten rat sarcoma(KRAS)G12D inhibi-tor MRTX1133 in combination with an SMAD3 inhibitor SIS3 against pancreatic carcinoma cells with KRAS G12D muta-tion,and to explore the underlying combining mechanism.METHODS:The potential affinity of MRTX1133 with KRAS G12D mutant protein was analyzed using molecular docking software.Cell viability was measured using Cell Counting Kit-8,and then the dose-effect curve and IC50 value were plotted.The combination index of MRTX1133 with SIS3 was calcu-lated using CompuSyn.The EdU incorporation assay was used to assess cell proliferation.Cell cycle profile and CD133-positive cell population was analyzed by flow cytometry.The invasion and migration of pancreatic carcinoma cells were de-tected using Transwell assays.Western blot was used to evaluated Jagged1(JAG1),NOTCH4 and aldehyde dehydroge-nase 1 family member A1(ALDH1A1)expression.RESULTS:The IC50 values of MRTX1133 were 0.894 µmol/L and 1.115 µmol/L in PANC-1 and SW1990 pancreatic carcinoma cells,respectively.Combined treatment with MRTX1133 and SIS3 showed the synergic effect.The combination of MRTX1133 with SIS3 reduced cell proliferation,delayed the pro-gression of cell cycle,and decreases the invasion and migration of pancreatic carcinoma cells.The CD133-positive cell population and ALDH1A1 expression were decreased in the combination group,suggesting that the combination of MRTX1133 with SIS3 can inhibit pancreatic carcinoma cell stemness.The mechanism study found that MRTX1133 in combination of SIS3 can inhibit JAG1 of NOTCH ligand expression.CONCLUSION:The combination of MRTX1133 with SIS3 affects NOTCH4 pathway and inhibits tumor stemness,thus showing the synergic effect against pancreatic carci-noma with KRAS G12D mutation.关键词
胰腺癌/MRTX1133/KRAS G12D突变/SMAD3蛋白Key words
pancreatic carcinoma/MRTX1133/KRAS G12D mutation/SMAD3 protein分类
医药卫生引用本文复制引用
张榜梅,蔡梅,王宏,章俊..MRTX1133联合SMAD3抑制剂作用于KRAS G12D突变胰腺癌细胞的机制研究[J].中国病理生理杂志,2026,42(3):417-427,11.基金项目
国家自然科学基金资助项目(No.82060565) （No.82060565）
病理形态及分子实验室项目(No.2025FYYJ-001) （No.2025FYYJ-001）
