# Turn off the error-prone repair that manufactures resistance mutations

Source: https://onco.cc/ideas/idea-bio1-mutagenesis-blockade-rev1/  
OnCo record `idea-bio1-mutagenesis-blockade-rev1` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## Sources

- Bottleneck evidence (Acquired resistance to every therapy): Soria et al., Osimertinib in untreated EGFR-mutated NSCLC (FLAURA, NEJM 2018): https://doi.org/10.1056/NEJMoa1713137

## Connected records

- pathways: [DNA damage response & homologous recombination](https://onco.cc/pathways/ddr/)
- terms: [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Mutational signature](https://onco.cc/terms/mutational-signature/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/)

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