Resistance to the KRAS^G12D Inhibitor MRTX1133 is Associated with Increased Sensitivity to BET Inhibition.

ABSTRACT: As many as 90% of human pancreatic ductal adenocarcinoma (PDAC) tumors harbor gain-of-function mutations in the KRAS oncogene. Recently, inhibitors of the most common KRAS mutation, KRAS^G12D, have entered the clinical arena. However, early evidence suggests that as monotherapy, KRAS^G12D inhibitors such as MRTX1133 at best provide brief periods of disease stabilization. Hence, there is a growing interest in understanding the mechanisms through which tumors acquire resistance to KRAS inhibition. In the present study, we generated in vitro models of MRTX1133 resistance and subjected parental and drug-resistant cell lines to RNA sequencing. This suggested that MRTX1133-resistant tumor cells undergo a global shift toward histone acetylation. Inhibition of the

SUBMITTER: Principe DR 

PROVIDER: S-EPMC12132508 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature