Oncogenic KRAS addiction states differentially influence MTH1 expression and 8-oxodGTPase activity in lung adenocarcinoma.

ABSTRACT: The efficacy of strategies targeting oncogenic RAS, prevalent in lung adenocarcinoma (LUAD), is limited by rapid adaptive resistance mechanisms. These include loss of RAS addiction and hyperactivation of downstream signaling pathways, such as PI3K/AKT. We previously reported that oncogenic RAS-driven LUAD cells possess an enhanced reliance on MTH1, the mammalian 8-oxodGTPase, to prevent genomic incorporation of oxidized nucleotides, and that MTH1 depletion compromises tumorigenesis and oncogenic signaling. Here, we show that elevated MTH1 correlates with poor prognosis in LUAD and that its redox-protective 8-oxodGTPase activity is variably regulated in KRAS-addicted vs. non-addicted states. Multiple oncogenic KRAS mutants or overexpression of wildtype (wt) KRAS increased MTH1 expression. C

SUBMITTER: Mateo-Victoriano B 

PROVIDER: S-EPMC11999683 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature