# Slow the tumour's mutation engine with APOBEC inhibitors during targeted therapy

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

## TL;DR

Subsets of lung, bladder and breast cancers carry raised APOBEC enzyme activity that keeps generating new mutations, feeding resistance. Blocking APOBEC3 alongside a targeted drug aims not to kill cells but to slow the rate at which resistant variants arise; the inhibitors are still in discovery.

## Summary

APOBEC3A and APOBEC3B mutagenesis is elevated in subsets of lung, bladder and breast cancers and has been mechanistically linked to acquired resistance to EGFR inhibitors in preclinical models. Small-molecule APOBEC3 inhibitors are in discovery. The proposal is an anti-evolution adjunct: combine an APOBEC inhibitor with the targeted agent from the first dose, with the aim not of killing cells but of reducing the rate at which resistant variants are generated.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: APOBEC3 inhibition during osimertinib treatment reduces the APOBEC-signature fraction of new mutations in progression samples and extends progression-free survival in APOBEC-high tumours.
- Rationale: Genetic APOBEC3A deletion delays resistance in EGFR-mutant xenografts; the signature is measurable in ctDNA, giving a pharmacodynamic biomarker and a patient-selection tool.
- Proposed test: Confirm in vivo delay of resistance with a tool compound across three driver models; if reproduced, a phase 1b of the first clinical APOBEC inhibitor with osimertinib in APOBEC-high EGFR-mutant lung cancer with serial ctDNA signature analysis.
- Maturity: preclinical-evidence
- Actor: industry

## Sources

- Bottleneck evidence (Tumour heterogeneity and clonal evolution): Gerlinger et al., Intratumor heterogeneity and branched evolution (NEJM 2012): https://doi.org/10.1056/NEJMoa1113205

## Connected records

- cancers: [Bladder & urothelial cancer](https://onco.cc/cancers/urothelial/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- drugs: [Osimertinib](https://onco.cc/drugs/osimertinib/)
- terms: [Mutational signature](https://onco.cc/terms/mutational-signature/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- key papers: [FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-flaura-nejm-2018/), [Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer](https://onco.cc/key-papers/paper-osimertinib-nsclc-n-engl-j-med-2017/), [Overall Survival with Osimertinib in Untreated, EGFR -Mutated Advanced NSCLC](https://onco.cc/key-papers/paper-osimertinib-nsclc-n-engl-j-med-2020/)

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