Slow the tumour's mutation engine with APOBEC inhibitors during targeted therapy
Many tumours carry an enzyme that keeps creating new mutations, feeding resistance. Blocking that enzyme while a targeted drug works could make resistance arrive later.
APOBEC3A and APOBEC3B mutagenesis is elevated in many 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.
- Tumour heterogeneity and clonal evolution · A tumour is many tumours. Treatments that kill most cells leave the rest to grow back, changed.
- Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.
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