Pseudomyxoma peritonei (PMP) is a rare disease characterized by a massive accumulation of mucus in the peritoneal cavity. The only effective treatment is aggressive surgery, aimed at removing all visible tumors. However, a high percentage of patients relapse, with subsequent progression and death. Recently, there has been an increase in therapies that target mutated oncogenic proteins. In this sense, KRAS has been reported to be highly mutated in PMP, with KRASG12D being the most common subtype. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in a high-grade PMP xenograft mouse model carrying a KRASG12D mutation. The results obtained in this work showed a profound inhibition of tumor growth, which was associated with a reduction in cell proliferation, an increase in apoptosis, and a reduction in the MAPK and PI3K/AKT/mTOR signaling pathways. In conclusion, these results demonstrate the high potency and efficacy of MRTX1133 in KRASG12D-PMP tumors and provide a rationale for clinical trials.

中文翻译：

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KRASG12D 小分子抑制剂在粘液性阑尾肿瘤异种移植模型中的抗肿瘤作用

腹膜假粘液瘤（PMP）是一种罕见疾病，其特征是腹膜腔内大量粘液积聚。唯一有效的治疗方法是积极的手术，旨在切除所有可见的肿瘤。然而，很大比例的患者会复发，随后病情进展并死亡。最近，针对突变致癌蛋白的疗法有所增加。从这个意义上说，KRAS 据报道在 PMP 中高度突变，其中 KRASG12D 是最常见的亚型。在这里，我们测试了小分子 KRASG12D 抑制剂 MRTX1133 在携带 KRASG12D 突变的高级 PMP 异种移植小鼠模型中的功效。这项工作中获得的结果显示对肿瘤生长的显着抑制，这与细胞增殖减少、细胞凋亡增加以及 MAPK 和 PI3K/AKT/mTOR 信号通路减少有关。总之，这些结果证明了 MRTX1133 在 KRASG12D-PMP 肿瘤中的高效力和功效，并为临床试验提供了理论依据。