# Drug resistance (primary and acquired)

Source: https://onco.cc/terms/resistance/  
OnCo record `resistance` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Term
- Last checked: 2026-09-04
- Also known as: 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

## 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).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Drug_resistance
- Wikipedia: https://en.wikipedia.org/wiki/Drug_resistance

## Connected records

- cancers: [ALK-positive non-small-cell lung cancer](https://onco.cc/cancers/alk-positive-nsclc/), [BRAF V600E-mutant non-small-cell lung cancer](https://onco.cc/cancers/braf-v600e-nsclc/), [BRCA or PALB2-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/brca-palb2-pdac/), [Chronic myeloid leukaemia (CML)](https://onco.cc/cancers/cml/), [Chronic myeloid leukaemia, accelerated and blast phase](https://onco.cc/cancers/cml-advanced-phase/), [EGFR-mutated non-small-cell lung cancer](https://onco.cc/cancers/egfr-mutant-nsclc/), [Gastrointestinal stromal tumour (GIST)](https://onco.cc/cancers/gist/), [KRAS G12C-mutant non-small-cell lung cancer](https://onco.cc/cancers/kras-g12c-nsclc/), [KRAS G12C-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-g12c-pdac/), [KRAS wild-type pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-wild-type-pdac/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [MET exon 14 and MET-amplified non-small-cell lung cancer](https://onco.cc/cancers/met-altered-nsclc/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Relapsed or refractory chronic lymphocytic leukaemia](https://onco.cc/cancers/cll-relapsed/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- key papers: [Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M](https://onco.cc/key-papers/paper-thress-nat-med/), [Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain](https://onco.cc/key-papers/paper-pao-egfr-t790m-acquired-resistance-plos-med-2005/), [ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer](https://onco.cc/key-papers/paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019/), [Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors](https://onco.cc/key-papers/paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017/), [Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers](https://onco.cc/key-papers/paper-yu-acquired-resistance-rebiopsy-egfr-ccr-2013/), [Androgen receptor pathway-independent prostate cancer is sustained through FGF signalling](https://onco.cc/key-papers/paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017/), [AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer](https://onco.cc/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/), [Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib](https://onco.cc/key-papers/paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018/), [Circulating tumour DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer](https://onco.cc/key-papers/paper-annala-ctdna-resistance-abiraterone-enzalutamide-cancer-discov-2018/), [Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas](https://onco.cc/key-papers/paper-lee-clonal-history-small-cell-transformation-jco-2017/), [CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug](https://onco.cc/key-papers/paper-codebreak-200-lancet-2023/), [CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer](https://onco.cc/key-papers/paper-codebreak-300-nejm-2023/), [Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes](https://onco.cc/key-papers/paper-offin-rb1-tp53-transformation-risk-jto-2019/), [DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer](https://onco.cc/key-papers/paper-dellphi-301-nejm-2023/), [EGFR mutation and resistance of non-small-cell lung cancer to gefitinib](https://onco.cc/key-papers/paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005/), [EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes](https://onco.cc/key-papers/paper-marcoux-egfr-small-cell-transformation-outcomes-jco-2019/), [First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer](https://onco.cc/key-papers/paper-shaw-crown-lorlatinib-crizotinib-nejm-2020/), [FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-flaura-nejm-2018/), [Genomic correlates of clinical outcome in advanced prostate cancer](https://onco.cc/key-papers/paper-abida-genomic-correlates-outcome-mcrpc-pnas-2019/), [Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors](https://onco.cc/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/), [Gerlinger: a single biopsy misses most of the mutations in a kidney tumour](https://onco.cc/key-papers/paper-gerlinger-intratumour-heterogeneity-nejm-2012/), [In vivo amplification of the androgen receptor gene and progression of human prostate cancer](https://onco.cc/key-papers/paper-visakorpi-androgen-receptor-amplification-nat-genet-1995/), [MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-mariposa-nejm-2024/), [MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling](https://onco.cc/key-papers/paper-engelman-met-amplification-gefitinib-resistance-science-2007/), [Molecular determinants of resistance to antiandrogen therapy](https://onco.cc/key-papers/paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004/), [Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer](https://onco.cc/key-papers/paper-gainor-alk-resistance-mutations-cancer-discov-2016/), [Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-labrecque-mcrpc-phenotypes-jci-2019/), [Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer](https://onco.cc/key-papers/paper-taplin-ar-mutation-androgen-independent-prostate-nejm-1995/), [Nuclear-localised androgen receptor splice variant 7 in circulating tumour cells as a predictive biomarker in castration-resistant prostate cancer](https://onco.cc/key-papers/paper-scher-nuclear-arv7-taxane-vs-arsi-jama-oncol-2018/), [Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities](https://onco.cc/key-papers/paper-gay-sclc-subtypes-inflamed-cancer-cell-2021/), [PROPHECY: prospective multicentre validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer](https://onco.cc/key-papers/paper-prophecy-arv7-validation-jco-2019/), [PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate](https://onco.cc/key-papers/paper-ferraldeschi-pten-protein-loss-abiraterone-eur-urol-2015/), [Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance](https://onco.cc/key-papers/paper-ku-rb1-trp53-lineage-plasticity-science-2017/), [Reciprocal feedback regulation of PI3K and androgen receptor signalling in PTEN-deficient prostate cancer](https://onco.cc/key-papers/paper-carver-pi3k-ar-reciprocal-feedback-prostate-cancer-cell-2011/), [Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F](https://onco.cc/key-papers/paper-shaw-alk-l1198f-resensitisation-nejm-2016/), [SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer](https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/), [Substantial interindividual and limited intraindividual genomic diversity among tumours from men with metastatic prostate cancer](https://onco.cc/key-papers/paper-kumar-interindividual-genomic-diversity-metastatic-prostate-nat-med-2016/)
- terms: [Amplification](https://onco.cc/terms/amplification/), [Antigen](https://onco.cc/terms/antigen/), [Antigen escape (antigen loss, lineage switch)](https://onco.cc/terms/antigen-escape/), [Antigen escape: how a lymphoma loses the thing the drug was aimed at](https://onco.cc/terms/lymphoma-bio-antigen-escape/), [BRCA reversion mutations](https://onco.cc/terms/brca-reversion-mutations/), [BTK C481S, PLCG2 and BCL2 G101V resistance mutations](https://onco.cc/terms/btki-bcl2i-resistance-mutations/), [Clonal evolution and the ecological view of cancer](https://onco.cc/terms/clonal-evolution-theory/), [Cross-resistance](https://onco.cc/terms/cross-resistance/), [Differentiation](https://onco.cc/terms/differentiation/), [Downstream and upstream](https://onco.cc/terms/downstream/), [EGFR C797S](https://onco.cc/terms/c797s/), [EGFRvIII](https://onco.cc/terms/egfrviii/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [Hormone therapy](https://onco.cc/terms/hormone-therapy/), [Inhibitor](https://onco.cc/terms/inhibitor/), [Kinase](https://onco.cc/terms/kinase/), [MET amplification (bypass resistance)](https://onco.cc/terms/met-amplification/), [On-target resistance mutations (gatekeeper, solvent-front, compound)](https://onco.cc/terms/gatekeeper-mutation/), [Progression](https://onco.cc/terms/progression/), [Refractory](https://onco.cc/terms/refractory/), [Relapsed / refractory (R/R)](https://onco.cc/terms/relapsed-refractory/), [Signalling pathway](https://onco.cc/terms/signalling-pathway/), [Targeted therapy](https://onco.cc/terms/targeted-therapy-term/)
- ideas: [An open atlas of collateral sensitivity for every approved targeted drug](https://onco.cc/ideas/idea-bio1-collateral-sensitivity-atlas/), [Autonomous closed-loop adaptive therapy driven by blood tests and evolutionary models](https://onco.cc/ideas/idea-moon-closed-loop-adaptive-therapy/), [Barcode patient-derived tumours to watch which clones win under each drug](https://onco.cc/ideas/idea-bio1-barcoded-avatars-clonal-fitness/), [Block the chemical switch that lets cells hide from treatment](https://onco.cc/ideas/idea-bio1-epigenetic-persister-blockade/), [Check whether a tumour can still show itself to the immune system](https://onco.cc/ideas/idea-bio2-antigen-presentation-triage/), [Cut off the emergency programme cancer cells use to survive treatment](https://onco.cc/ideas/idea-bio1-stress-response-blockade/), [Every resistance mechanism found in a patient must be rebuilt in the laboratory](https://onco.cc/ideas/idea-bio1-reverse-translation-resistance-models/), [Evolution-guided 'adaptive therapy' dosing tested in randomised phase 2 trials](https://onco.cc/ideas/idea-tr1-adaptive-therapy-randomised-phase-2/), [Find the parts of a tumour the drug never reaches](https://onco.cc/ideas/idea-bio1-drug-exposure-sanctuary-mapping/), [Forecast the next resistance mutation like the weather](https://onco.cc/ideas/idea-bio1-evolution-forecasting/), [Fund a biopsy at progression, every time, as standard care](https://onco.cc/ideas/idea-bio1-mandatory-progression-biopsy/), [Kill drug-tolerant persisters through ferroptosis](https://onco.cc/ideas/idea-ferroptosis-persisters/), [Kill the sleeping survivor cells with iron-dependent cell death](https://onco.cc/ideas/idea-bio1-persister-ferroptosis/), [Make post-progression sampling a condition of accelerated approval](https://onco.cc/ideas/idea-bio1-approval-linked-progression-sampling/), [Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became](https://onco.cc/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/), [One open atlas of how tumours escape every drug](https://onco.cc/ideas/idea-bio1-open-resistance-atlas/), [Pause a failed drug so the tumour becomes sensitive to it again](https://onco.cc/ideas/idea-bio1-drug-holiday-resensitisation/), [SMART designs to test treatment strategies, not just single drugs](https://onco.cc/ideas/idea-tr1-smart-designs-for-adaptive-strategies/), [Starve the survivors: target the energy pathway drug-tolerant cells switch to](https://onco.cc/ideas/idea-bio1-persister-metabolic-vulnerability/), [Test intermittent dosing of targeted drugs to delay resistance, with honest priors](https://onco.cc/ideas/idea-tr1-intermittent-dosing-to-delay-resistance/), [Treat resistance like an infectious disease and run national surveillance](https://onco.cc/ideas/idea-bio1-real-world-resistance-surveillance/), [Turn off the error-prone repair that manufactures resistance mutations](https://onco.cc/ideas/idea-bio1-mutagenesis-blockade-rev1/), [Vaccinate against the resistance mutation before it takes over](https://onco.cc/ideas/idea-bio1-resistance-mutation-vaccine/)
- biomarkers: [ALK kinase-domain resistance mutation (G1202R and the rest)](https://onco.cc/biomarkers/alk-resistance-mutation/), [AR amplification (gene and upstream enhancer)](https://onco.cc/biomarkers/ar-amplification/), [AR ligand-binding-domain mutation (L702H, W742C, H875Y, T878A, F877L)](https://onco.cc/biomarkers/ar-ligand-binding-domain-mutation/), [BCL2 G101V and the other venetoclax binding-site mutations](https://onco.cc/biomarkers/bcl2-g101v/), [BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors](https://onco.cc/biomarkers/btk-c481s/), [EGFR C797S (and its phase with T790M)](https://onco.cc/biomarkers/egfr-c797s/), [STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma](https://onco.cc/biomarkers/stk11-keap1-loss/), [Treatment-emergent neuroendocrine transformation (recognising it)](https://onco.cc/biomarkers/nepc-transformation/)
- trials: [AURA3](https://onco.cc/trials/aura3/), [IMpower150](https://onco.cc/trials/impower150/)
- targets: [ALK](https://onco.cc/targets/alk/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Drug efflux pumps (ABC transporters)](https://onco.cc/pathways/drug-efflux-pumps/), [Drug-tolerant persister cells](https://onco.cc/pathways/drug-tolerant-persisters/), [Epithelial-mesenchymal transition & drug efflux](https://onco.cc/pathways/emt/), [Ferroptosis & regulated cell death](https://onco.cc/pathways/ferroptosis-cell-death/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)
- people: [Robert A. Gatenby](https://onco.cc/people/robert-gatenby/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- institutions: [Istituto di Candiolo IRCCS (FPO)](https://onco.cc/institutions/candiolo/)
- roadmaps: [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)

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