{"entity":{"id":"idea-bio1-apobec-inhibitor-adjunct","kind":"idea","name":"Slow the tumour's mutation engine with APOBEC inhibitors during targeted therapy","aka":[],"tldr":"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.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Tumour heterogeneity and clonal evolution): Gerlinger et al., Intratumor heterogeneity and branched evolution (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1113205"}],"tags":[],"related":[],"cancers":["nsclc","urothelial"],"sections":[],"technologies":[],"targets":[],"drugs":["osimertinib"],"companies":[],"institutions":[],"pathways":[],"terms":["mutational-signature"],"trials":[],"people":[],"bottlenecks":["b-tumor-heterogeneity","b-resistance"],"keyPapers":["paper-flaura-nejm-2018","paper-osimertinib-nsclc-n-engl-j-med-2017","paper-osimertinib-nsclc-n-engl-j-med-2020"],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"large","horizonYears":7},"route":"/ideas/idea-bio1-apobec-inhibitor-adjunct/","neighbours":{"cancer":[{"id":"urothelial","kind":"cancer","name":"Bladder & urothelial cancer","route":"/cancers/urothelial/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"drug":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}],"term":[{"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/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}],"paper":[{"id":"paper-flaura-nejm-2018","kind":"paper","name":"FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer","route":"/key-papers/paper-flaura-nejm-2018/"},{"id":"paper-osimertinib-nsclc-n-engl-j-med-2017","kind":"paper","name":"Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer","route":"/key-papers/paper-osimertinib-nsclc-n-engl-j-med-2017/"},{"id":"paper-osimertinib-nsclc-n-engl-j-med-2020","kind":"paper","name":"Overall Survival with Osimertinib in Untreated, EGFR -Mutated Advanced NSCLC","route":"/key-papers/paper-osimertinib-nsclc-n-engl-j-med-2020/"}]}}