Whole exome sequencing of murine cell lines after long-term treatment with a mismatch repair inhibitor
Long-term pharmacological inhibition of PMS2 was evaluated by whole-exome sequencing to assess the genomic consequences of sustained mismatch repair (MMR) blockade. Computational analyses revealed a progressive, time-dependent increase in tumor mutational burden driven by the accumulation of single nucleotide variants. Importantly, MMR inhibited  cells acquired canonical features of MMR deficiency, including enrichment of MMR deficient-associated mutational signatures and the emergence of microsatellite instability status. These findings demonstrate that pharmacological inhibition of PMS2 recapitulates the genomic architecture of MMR-deficient tumors, supporting the concept that MMR can be therapeutically modulated to induce a hypermutated, immunogenic state.
Long-term pharmacological inhibition of PMS2 was evaluated by whole-exome sequencing to assess the genomic consequences of sustained mismatch repair (MMR) blockade. Computational analyses revealed a progressive, time-dependent increase in tumor mutational burden driven by the accumulation of single nucleotide variants. Importantly, MMR inhibited  cells acquired canonical features of MMR deficiency, including enrichment of MMR deficient-associated mutational signatures and the emergence of microsatellite instability status. These findings demonstrate that pharmacological inhibition of PMS2 recapitulates the genomic architecture of MMR-deficient tumors, supporting the concept that MMR can be therapeutically modulated to induce a hypermutated, immunogenic state.
Candiolo Cancer Institute