Antimetastatic effects of MRTX1133 KRAS G12D specific inhibitor in a liver metastatic model of pancreatic ductal adenocarcinoma

MRTX1133 is a first-in-class KRAS G12D inhibitor being in phase I/II clinical trials. KRAS is the most frequently mutated oncogene in pancreatic ductal adenocarcinoma (PDAC), with a predominance of the G12D variant. PDAC is a highly lethal Cancer type with an extremely low 5-year survival rate. Although PDAC metastasis most frequently targets the liver, the influence of MRTX1133 treatment on hepatic metastases has not yet been investigated thoroughly. Thus, we aimed to analyze the effect of MRTX1133 treatment on local tumor growth and liver metastasis development. Cell proliferation and migration were investigated in vitro using clonogenic, scratch, Boyden chamber, and immunoblot assay in three KRAS G12D mutated PDAC cell lines (ASPC1, SW1990, PANC1). Moreover, PANC1 was examined in vivo in a spleen-to-liver metastatic xenograft model using NXG female mice. The MRTX1133 treatment decreased clonogenic proliferation and migratory activity; furthermore, it inhibited both local tumor growth in the spleen and liver colonization. MRTX1133 induced alterations associated with mesenchymal-to-epithelial transition; furthermore, lower levels of activated ERK, altered FAK expression, and activation were observed. In addition to the antiproliferative effects of MRTX1133, our in vitro and in vivo results indicate the importance of MRTX1133 as a potential antimetastatic drug in PDAC therapy.

Epithelial-mesenchymal transition; KRAS; MRTX1133; Metastasis; Pancreatic cancer.