在 sotorasib 开发出来之前，Kirsten 大鼠肉瘤 (KRAS) 致癌基因被认为是“不可成药的”，sotorasib 是一种 KRASG12C 选择性抑制剂，对肺癌显示出良好的效果。 MRTX1133是一种新型KRASG12D抑制剂，尽管单独使用时对胰腺癌的作用有限，但在基础研究中已显示出有希望的结果。因此，迫切需要寻找可与KRAS抑制剂联合使用的有效药物。在这项研究中，我们发现服用 KRAS 抑制剂 sotorasib 或 MRTX1133 上调 STAT3 磷酸化并通过反馈反应重新激活 ERK。添加MEK抑制剂trametinib和JAK2抑制剂fedratinib成功逆转了这种效应，并在体外和体内产生了显着的生长抑制。对 sotorasib 和 MRTX1133 耐药细胞的分析表明，曲美替尼加 fedratinib 可逆转对 sotorasib 或 MRTX1133 的耐药性。这些发现表明，JAK2 介导的通路和 MAPK 通路的重新激活可能在胰腺癌对 KRAS 抑制剂的耐药性中发挥关键作用。因此，同时抑制 KRAS、MEK 和 JAK2 可能是针对 KRAS 突变胰腺癌的创新治疗策略。© 2024 作者。约翰·威利出版的《分子肿瘤学》

The Kirsten rat sarcoma (KRAS) oncogene was considered "undruggable" until the development of sotorasib, a KRASG12C selective inhibitor that shows favorable effects against lung cancers. MRTX1133, a novel KRASG12D inhibitor, has shown promising results in basic research, although its effects against pancreatic cancer are limited when used alone. Therefore, there is an urgent need to identify effective drugs that can be used in combination with KRAS inhibitors. In this study, we found that administration of the KRAS inhibitors sotorasib or MRTX1133 upregulated STAT3 phosphorylation and reactivated ERK through a feedback reaction. The addition of the MEK inhibitor trametinib and the JAK2 inhibitor fedratinib successfully reversed this effect and resulted in significant growth inhibition in vitro and in vivo. Analyses of sotorasib- and MRTX1133-resistant cells showed that trametinib plus fedratinib reversed the resistance to sotorasib or MRTX1133. These findings suggest that the JAK2-mediated pathway and reactivation of the MAPK pathway may play key roles in resistance to KRAS inhibitors in pancreatic cancers. Accordingly, simultaneous inhibition of KRAS, MEK, and JAK2 could be an innovative therapeutic strategy against KRAS-mutant pancreatic cancer.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.