{"entity":{"id":"idea-bio1-mutagenesis-blockade-rev1","kind":"idea","name":"Turn off the error-prone repair that manufactures resistance mutations","aka":[],"tldr":"Under treatment stress, cancer cells switch on sloppy DNA copying that generates the mutations they need to survive. Blocking that machinery could stop resistance being invented.","summary":"Stress-induced mutagenesis through translesion synthesis polymerases (REV1, POLZ) accelerates the emergence of resistance in bacteria and in cancer cells. REV1 inhibitors have been described and shown to reduce chemotherapy-induced mutagenesis and delay resistance in models. Given as an adjunct rather than a cytotoxic, the aim is to lower the mutation supply rate rather than to kill cells.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Acquired resistance to every therapy): Soria et al., Osimertinib in untreated EGFR-mutated NSCLC (FLAURA, NEJM 2018)","url":"https://doi.org/10.1056/NEJMoa1713137"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["ddr"],"terms":["mutational-signature","resistance"],"trials":[],"people":[],"bottlenecks":["b-resistance"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Co-administration of a translesion synthesis inhibitor with chemotherapy or targeted therapy reduces the acquisition of new resistance mutations and prolongs time to progression in vivo.","rationale":"Resistance requires variation; reducing the rate at which variation is generated is a validated strategy against bacterial resistance and has direct molecular counterparts in cancer.","test":"In vivo resistance-emergence studies with and without a REV1 inhibitor, using barcoded models to distinguish selection of pre-existing clones from newly generated mutations.","maturity":"preclinical-evidence","actor":"research","cost":"medium","horizonYears":7},"route":"/ideas/idea-bio1-mutagenesis-blockade-rev1/","neighbours":{"pathway":[{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","route":"/pathways/ddr/"}],"term":[{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"mutational-signature","kind":"term","name":"Mutational signature","route":"/terms/mutational-signature/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"}]}}