Synthetic lethal therapy reveals precision therapeutic strategy for MSH2-mutated bladder cancer

ABSTRACT: hMSH2 (human mutS homolog 2) is the most frequently mutated gene in the DNA mismatch repair (MMR) system in bladder cancer (BCa). The majority of hMSH2 mutations result in a reduction of expression and a consequent promote cisplatin (CDDP) chemoresistance. However, precision therapeutic strategy based on hMSH2 mutations is not available clinically. Herein, we reported that knockout of hMSH2 mediated by CRISPR/cas9 technology reduced the sensitivity of BCa to CDDP. Importantly, GK921, a TGM2-specific inhibitor, increased tumor cell killing by CDDP in hMSH2-deficient BCa in a synthetic lethal manner. GK921 also promoted the chemosensitivity of Msh2-knockout mice to CDDP. Hi-C analysis indicated that hMSH2 deficiency rewired chromatin accessibility of the TGM2 promoter region, which recruits more transcription factors. The enrichment levels of transcription factor AP-1 in TGM2 promoter region were increased in hMSH2-knockout BCa cells, thereby promoting the expression of TGM2 transcriptionally. This study shows that CDDP effectiveness depends on TGM2 levels in hMSH2-mutated BCa and that combining CDDP with TGM2 inhibition may provide a promising personalized therapeutic strategy for hMSH2-mutated BCa patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262994 | GEO | 2026/06/30

REPOSITORIES: GEO