{"entity":{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","aka":["acquired resistance","primary resistance","adaptive resistance","pre-existing resistance","resistance mechanism","resistance mechanisms","resistant clone","resistant clones","resistant subclone","resistant subclones","bypass pathways","bypass signalling","bypass resistance","chemoresistance","chemoresistant","chemotherapy resistance","TKI resistance","TKI-resistant","drug-resistant","therapy-resistant","become resistant","becomes resistant","escape mechanism","escape mechanisms","escape mutation","escape mutations","reversion mutations","BRCA reversion","on-target mutations","compound resistance mutations","confers resistance","emergence of resistance","overcome resistance","resistance alteration","resistance pathway","resistant disease"],"tldr":"Why cancer drugs stop working: the tumour either never depended on the target or evolves around the block.","summary":"Primary: no target dependence, poor drug penetration, pre-existing resistant clones. Acquired: on-target mutations (EGFR T790M/C797S, ESR1, BRCA reversion, ALK G1202R), bypass signalling (MET amplification), lineage change (SCLC transformation), antigen loss (CD19-negative relapse), efflux, epigenetic plasticity. Tumours are evolving populations; combination and sequential strategies are the response.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Drug_resistance","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Drug_resistance"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["kinase-inhibitors","liquid-biopsy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-yu-acquired-resistance-rebiopsy-egfr-ccr-2013","paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018","paper-gainor-alk-resistance-mutations-cancer-discov-2016","paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019"],"journals":[],"dependsOn":[],"notes":["Lung cancer is where acquired resistance is best characterised, in three categories with three different consequences. On-target mutation (EGFR T790M in 63% of first-generation rebiopsies, then C797S in 22% of osimertinib resistance; ALK G1202R after a second-generation inhibitor) means the tumour still depends on the target and a later-generation inhibitor is the answer. Bypass activation (MET amplification in 5 to 22%, HER2 amplification in 13%) means adding a second inhibitor rather than swapping. Lineage change (small-cell transformation in 3 to 14%) means a different disease and a different chemotherapy. Which one it is cannot be guessed, which is why rebiopsy or plasma genotyping at progression is standard (Yu 2013, Oxnard 2018, Gainor 2016, Shaw 2019)."],"category":"Resistance"},"route":"/terms/resistance/","neighbours":{"cancer":[{"id":"alk-positive-nsclc","kind":"cancer","name":"ALK-positive non-small-cell lung cancer","route":"/cancers/alk-positive-nsclc/"},{"id":"braf-v600e-nsclc","kind":"cancer","name":"BRAF V600E-mutant non-small-cell lung cancer","route":"/cancers/braf-v600e-nsclc/"},{"id":"brca-palb2-pdac","kind":"cancer","name":"BRCA or PALB2-mutant pancreatic ductal adenocarcinoma","route":"/cancers/brca-palb2-pdac/"},{"id":"cml","kind":"cancer","name":"Chronic myeloid leukaemia (CML)","route":"/cancers/cml/"},{"id":"cml-advanced-phase","kind":"cancer","name":"Chronic myeloid leukaemia, accelerated and blast phase","route":"/cancers/cml-advanced-phase/"},{"id":"egfr-mutant-nsclc","kind":"cancer","name":"EGFR-mutated non-small-cell lung 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adenocarcinoma","route":"/cancers/metastatic-pdac/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"},{"id":"cll-relapsed","kind":"cancer","name":"Relapsed or refractory chronic lymphocytic leukaemia","route":"/cancers/cll-relapsed/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"paper":[{"id":"paper-thress-nat-med","kind":"paper","name":"Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR 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at","route":"/terms/lymphoma-bio-antigen-escape/"},{"id":"brca-reversion-mutations","kind":"term","name":"BRCA reversion mutations","route":"/terms/brca-reversion-mutations/"},{"id":"btki-bcl2i-resistance-mutations","kind":"term","name":"BTK C481S, PLCG2 and BCL2 G101V resistance mutations","route":"/terms/btki-bcl2i-resistance-mutations/"},{"id":"clonal-evolution-theory","kind":"term","name":"Clonal evolution and the ecological view of cancer","route":"/terms/clonal-evolution-theory/"},{"id":"cross-resistance","kind":"term","name":"Cross-resistance","route":"/terms/cross-resistance/"},{"id":"differentiation","kind":"term","name":"Differentiation","route":"/terms/differentiation/"},{"id":"downstream","kind":"term","name":"Downstream and upstream","route":"/terms/downstream/"},{"id":"c797s","kind":"term","name":"EGFR C797S","route":"/terms/c797s/"},{"id":"egfrviii","kind":"term","name":"EGFRvIII","route":"/terms/egfrviii/"},{"id":"histologic-transformation","kind":"term","name":"Histologic transformation","route":"/terms/histologic-transformation/"},{"id":"hormone-therapy","kind":"term","name":"Hormone therapy","route":"/terms/hormone-therapy/"},{"id":"inhibitor","kind":"term","name":"Inhibitor","route":"/terms/inhibitor/"},{"id":"kinase","kind":"term","name":"Kinase","route":"/terms/kinase/"},{"id":"met-amplification","kind":"term","name":"MET amplification (bypass resistance)","route":"/terms/met-amplification/"},{"id":"gatekeeper-mutation","kind":"term","name":"On-target resistance mutations (gatekeeper, solvent-front, compound)","route":"/terms/gatekeeper-mutation/"},{"id":"progression","kind":"term","name":"Progression","route":"/terms/progression/"},{"id":"refractory","kind":"term","name":"Refractory","route":"/terms/refractory/"},{"id":"relapsed-refractory","kind":"term","name":"Relapsed / refractory (R/R)","route":"/terms/relapsed-refractory/"},{"id":"signalling-pathway","kind":"term","name":"Signalling pathway","route":"/terms/signalling-pathway/"},{"id":"targeted-therapy-term","kind":"term","name":"Targeted therapy","route":"/terms/targeted-therapy-term/"}],"idea":[{"id":"idea-bio1-collateral-sensitivity-atlas","kind":"idea","name":"An open atlas of collateral sensitivity for every approved targeted drug","route":"/ideas/idea-bio1-collateral-sensitivity-atlas/"},{"id":"idea-moon-closed-loop-adaptive-therapy","kind":"idea","name":"Autonomous closed-loop adaptive therapy driven by blood tests and evolutionary models","route":"/ideas/idea-moon-closed-loop-adaptive-therapy/"},{"id":"idea-bio1-barcoded-avatars-clonal-fitness","kind":"idea","name":"Barcode patient-derived tumours to watch which clones win under each drug","route":"/ideas/idea-bio1-barcoded-avatars-clonal-fitness/"},{"id":"idea-bio1-epigenetic-persister-blockade","kind":"idea","name":"Block the chemical switch that lets cells hide from treatment","route":"/ideas/idea-bio1-epigenetic-persister-blockade/"},{"id":"idea-bio2-antigen-presentation-triage","kind":"idea","name":"Check whether a tumour can still show itself to the immune system","route":"/ideas/idea-bio2-antigen-presentation-triage/"},{"id":"idea-bio1-stress-response-blockade","kind":"idea","name":"Cut off the emergency programme cancer cells use to survive treatment","route":"/ideas/idea-bio1-stress-response-blockade/"},{"id":"idea-bio1-reverse-translation-resistance-models","kind":"idea","name":"Every resistance mechanism found in a patient must be rebuilt in the laboratory","route":"/ideas/idea-bio1-reverse-translation-resistance-models/"},{"id":"idea-tr1-adaptive-therapy-randomised-phase-2","kind":"idea","name":"Evolution-guided 'adaptive therapy' dosing tested in randomised phase 2 trials","route":"/ideas/idea-tr1-adaptive-therapy-randomised-phase-2/"},{"id":"idea-bio1-drug-exposure-sanctuary-mapping","kind":"idea","name":"Find the parts of a tumour the drug never reaches","route":"/ideas/idea-bio1-drug-exposure-sanctuary-mapping/"},{"id":"idea-bio1-evolution-forecasting","kind":"idea","name":"Forecast the next resistance mutation like the weather","route":"/ideas/idea-bio1-evolution-forecasting/"},{"id":"idea-bio1-mandatory-progression-biopsy","kind":"idea","name":"Fund a biopsy at progression, every time, as standard care","route":"/ideas/idea-bio1-mandatory-progression-biopsy/"},{"id":"idea-ferroptosis-persisters","kind":"idea","name":"Kill drug-tolerant persisters through ferroptosis","route":"/ideas/idea-ferroptosis-persisters/"},{"id":"idea-bio1-persister-ferroptosis","kind":"idea","name":"Kill the sleeping survivor cells with iron-dependent cell death","route":"/ideas/idea-bio1-persister-ferroptosis/"},{"id":"idea-bio1-approval-linked-progression-sampling","kind":"idea","name":"Make post-progression sampling a condition of accelerated approval","route":"/ideas/idea-bio1-approval-linked-progression-sampling/"},{"id":"idea-lung-resistance-directed-sequencing-at-every-progression","kind":"idea","name":"Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became","route":"/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/"},{"id":"idea-bio1-open-resistance-atlas","kind":"idea","name":"One open atlas of how tumours escape every drug","route":"/ideas/idea-bio1-open-resistance-atlas/"},{"id":"idea-bio1-drug-holiday-resensitisation","kind":"idea","name":"Pause a failed drug so the tumour becomes sensitive to it again","route":"/ideas/idea-bio1-drug-holiday-resensitisation/"},{"id":"idea-tr1-smart-designs-for-adaptive-strategies","kind":"idea","name":"SMART designs to test treatment strategies, not just single drugs","route":"/ideas/idea-tr1-smart-designs-for-adaptive-strategies/"},{"id":"idea-bio1-persister-metabolic-vulnerability","kind":"idea","name":"Starve the survivors: target the energy pathway drug-tolerant cells switch to","route":"/ideas/idea-bio1-persister-metabolic-vulnerability/"},{"id":"idea-tr1-intermittent-dosing-to-delay-resistance","kind":"idea","name":"Test intermittent dosing of targeted drugs to delay resistance, with honest priors","route":"/ideas/idea-tr1-intermittent-dosing-to-delay-resistance/"},{"id":"idea-bio1-real-world-resistance-surveillance","kind":"idea","name":"Treat resistance like an infectious disease and run national surveillance","route":"/ideas/idea-bio1-real-world-resistance-surveillance/"},{"id":"idea-bio1-mutagenesis-blockade-rev1","kind":"idea","name":"Turn off the error-prone repair that manufactures resistance 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L528W and T474I after the non-covalent inhibitors","route":"/biomarkers/btk-c481s/"},{"id":"egfr-c797s","kind":"biomarker","name":"EGFR C797S (and its phase with T790M)","route":"/biomarkers/egfr-c797s/"},{"id":"stk11-keap1-loss","kind":"biomarker","name":"STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma","route":"/biomarkers/stk11-keap1-loss/"},{"id":"nepc-transformation","kind":"biomarker","name":"Treatment-emergent neuroendocrine transformation (recognising it)","route":"/biomarkers/nepc-transformation/"}],"trial":[{"id":"aura3","kind":"trial","name":"AURA3","route":"/trials/aura3/"},{"id":"impower150","kind":"trial","name":"IMpower150","route":"/trials/impower150/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"drug-efflux-pumps","kind":"pathway","name":"Drug efflux pumps (ABC transporters)","route":"/pathways/drug-efflux-pumps/"},{"id":"drug-tolerant-persisters","kind":"pathway","name":"Drug-tolerant persister cells","route":"/pathways/drug-tolerant-persisters/"},{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"ferroptosis-cell-death","kind":"pathway","name":"Ferroptosis & regulated cell death","route":"/pathways/ferroptosis-cell-death/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"person":[{"id":"robert-gatenby","kind":"person","name":"Robert A. Gatenby","route":"/people/robert-gatenby/"}],"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/"}],"institution":[{"id":"candiolo","kind":"institution","name":"Istituto di Candiolo IRCCS (FPO)","route":"/institutions/candiolo/"}],"roadmap":[{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}