Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines.

ABSTRACT: Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of Kras^G12D;Pik3ca^H1047R or Trp53^R172H and/or ablation of Pten or Trp53. We find that Kras^G12D;Pik3ca^H1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling i

SUBMITTER: Huber A 

PROVIDER: S-EPMC11372443 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature