{"entity":{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","aka":[],"tldr":"When a drug blocks a cancer's engine, the cancer has five ways back: change the part the drug binds, make more of it, take a side road, switch to a different engine altogether, or stop letting the drug in. Knowing which route a tumour took decides the next drug.","summary":"Vasan, Baselga and Hyman's framework. (1) On-target: secondary mutations that block binding (EGFR T790M and C797S, ALK G1202R, BTK C481S, KRAS Y96D, ESR1 ligand-domain, AR F877L, BCR-ABL T315I) or amplification of the target (AR, BCR-ABL, MET after MET inhibition, BRAF splice variants). (2) Bypass: a parallel input restores the downstream signal (MET or HER3 amplification under EGFR blockade, RTK upregulation via loss of ERK feedback after BRAF/MEK inhibition, NRG1 fusions, IGF1R). (3) Downstream: mutation or amplification below the block (KRAS/NRAS, PIK3CA, MAP2K1, PTEN loss, CDK4/cyclin E, RB1 loss under CDK4/6 inhibition). (4) Phenotypic: lineage plasticity (neuroendocrine transformation, EMT, squamous transdifferentiation) or entry into a drug-tolerant persister state that no longer depends on the target. (5) Pharmacological/antigenic: efflux pumps, sanctuary sites (brain), drug metabolism, and for immune therapies antigen loss (CD19, BCMA, B2M) or payload-related mechanisms for ADCs (SLFN11 loss, TOP1 mutation, antigen downregulation). Pre-existing resistant subclones are selected (clonal evolution) and new mutations arise under APOBEC-driven mutagenesis. Countermeasures: next-generation inhibitors, vertical combinations (BRAF+MEK, KRAS+EGFR), parallel combinations, ctDNA-guided switching, and non-cross-resistant modalities (ADCs, radioligands, cell therapy).","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Drug_resistance","links":[{"label":"Vasan, Baselga & Hyman, A view on drug resistance in cancer (Nature 2019)","url":"https://doi.org/10.1038/s41586-019-1730-1"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["nsclc","non-hodgkin-lymphoma"],"sections":[],"technologies":["liquid-biopsy","cgp","kinase-inhibitors","adc","radioligand-therapy","car-t"],"targets":["egfr","alk","kras","met","her3","pik3ca","estrogen-receptor","androgen-receptor","btk","bcr-abl","cd19","bcma","dll3"],"drugs":["osimertinib","lorlatinib","amivantamab","pirtobrutinib","asciminib","sotorasib","cetuximab","elacestrant","tarlatamab"],"companies":[],"institutions":[],"pathways":["rtk-activation","ras-mapk","clonal-evolution","drug-tolerant-persisters","drug-efflux-pumps","lineage-plasticity-neuroendocrine","antigen-presentation-immunoediting"],"terms":["resistance","c797s","met-amplification","esr1-mutation","ar-v7","efflux-pump","histologic-transformation","oligoprogression"],"trials":[],"people":[],"bottlenecks":["b-resistance","b-tumor-heterogeneity"],"keyPapers":["paper-vasan-nature"],"journals":[],"dependsOn":[],"notes":[],"analogy":"Blocking a motorway. Traffic re-routes through a changed junction (target mutation), an extra lane (amplification), a parallel A-road (bypass), a road further along (downstream), a different form of transport (lineage switch), or simply avoids the roadblock's jurisdiction (efflux, sanctuary sites).","nodes":[{"id":"drug","label":"Drug blocks target","x":45,"y":8,"targetId":"egfr"},{"id":"target","label":"Target → signal → growth","x":45,"y":40},{"id":"ontarget","label":"1 Target mutation / amp","x":12,"y":25,"targetId":"kras"},{"id":"bypass","label":"2 Bypass RTK (MET, HER3)","x":12,"y":55,"targetId":"met"},{"id":"down","label":"3 Downstream (PIK3CA, RB1)","x":12,"y":85,"targetId":"pik3ca"},{"id":"pheno","label":"4 Lineage switch, persisters","x":78,"y":25,"targetId":"dll3"},{"id":"pharm","label":"5 Efflux, sanctuary, antigen loss","x":78,"y":55,"targetId":"cd19"},{"id":"growth","label":"Regrowth under therapy","x":45,"y":72},{"id":"counter","label":"Next-gen, vertical combos, switch","x":78,"y":88}],"edges":[{"from":"drug","to":"target","type":"inhibits"},{"from":"target","to":"growth","type":"activates"},{"from":"ontarget","to":"drug","type":"inhibits"},{"from":"bypass","to":"growth","type":"activates"},{"from":"down","to":"growth","type":"activates"},{"from":"pheno","to":"growth","type":"activates"},{"from":"pharm","to":"drug","type":"inhibits"},{"from":"counter","to":"growth","type":"inhibits"}],"interventions":["Next-generation inhibitors for on-target mutations (osimertinib for T790M, lorlatinib for ALK G1202R, pirtobrutinib for BTK C481S, asciminib for T315I)","Vertical and parallel combinations: BRAF+MEK, KRAS G12C + EGFR in CRC, CDK4/6 + endocrine + PI3K/AKT","Switching modality on progression: ADCs, radioligands, engagers and CAR-T are not cross-resistant with small molecules","Serial ctDNA to detect the route (C797S, MET amp, ESR1) and adaptive dosing; see the resistance atlas for every class"]},"route":"/pathways/resistance-routes-map/","neighbours":{"cancer":[{"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/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"car-t","kind":"technology","name":"CAR-T cell therapy","route":"/technologies/car-t/"},{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"radioligand-therapy","kind":"technology","name":"Radioligand therapy (beta emitters)","route":"/technologies/radioligand-therapy/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"},{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"bcma","kind":"target","name":"BCMA","route":"/targets/bcma/"},{"id":"bcr-abl","kind":"target","name":"BCR::ABL1 (Philadelphia chromosome)","route":"/targets/bcr-abl/"},{"id":"btk","kind":"target","name":"BTK (Bruton tyrosine kinase)","route":"/targets/btk/"},{"id":"cd19","kind":"target","name":"CD19","route":"/targets/cd19/"},{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"estrogen-receptor","kind":"target","name":"Estrogen receptor (ERα)","route":"/targets/estrogen-receptor/"},{"id":"fak","kind":"target","name":"FAK (PTK2)","route":"/targets/fak/"},{"id":"her3","kind":"target","name":"HER3","route":"/targets/her3/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"met","kind":"target","name":"MET","route":"/targets/met/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"shp2","kind":"target","name":"SHP2 (PTPN11)","route":"/targets/shp2/"}],"drug":[{"id":"amivantamab","kind":"drug","name":"Amivantamab","route":"/drugs/amivantamab/"},{"id":"asciminib","kind":"drug","name":"Asciminib","route":"/drugs/asciminib/"},{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"},{"id":"elacestrant","kind":"drug","name":"Elacestrant","route":"/drugs/elacestrant/"},{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"pirtobrutinib","kind":"drug","name":"Pirtobrutinib","route":"/drugs/pirtobrutinib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"},{"id":"tarlatamab","kind":"drug","name":"Tarlatamab","route":"/drugs/tarlatamab/"}],"pathway":[{"id":"antigen-presentation-immunoediting","kind":"pathway","name":"Antigen presentation & immune editing","route":"/pathways/antigen-presentation-immunoediting/"},{"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":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"term":[{"id":"lymphoma-bio-antigen-escape","kind":"term","name":"Antigen escape: how a lymphoma loses the thing the drug was aimed at","route":"/terms/lymphoma-bio-antigen-escape/"},{"id":"ar-v7","kind":"term","name":"AR-V7 splice variant","route":"/terms/ar-v7/"},{"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":"efflux-pump","kind":"term","name":"Drug efflux pumps (ABC transporters)","route":"/terms/efflux-pump/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"c797s","kind":"term","name":"EGFR C797S","route":"/terms/c797s/"},{"id":"esr1-mutation","kind":"term","name":"ESR1 mutation","route":"/terms/esr1-mutation/"},{"id":"histologic-transformation","kind":"term","name":"Histologic transformation","route":"/terms/histologic-transformation/"},{"id":"met-amplification","kind":"term","name":"MET amplification (bypass resistance)","route":"/terms/met-amplification/"},{"id":"oligoprogression","kind":"term","name":"Oligoprogression","route":"/terms/oligoprogression/"}],"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-vasan-nature","kind":"paper","name":"A view on drug resistance in cancer","route":"/key-papers/paper-vasan-nature/"},{"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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kinase-domain resistance mutation (G1202R and the rest)","route":"/biomarkers/alk-resistance-mutation/"},{"id":"ar-amplification","kind":"biomarker","name":"AR amplification (gene and upstream enhancer)","route":"/biomarkers/ar-amplification/"},{"id":"ar-ligand-binding-domain-mutation","kind":"biomarker","name":"AR ligand-binding-domain mutation (L702H, W742C, H875Y, T878A, F877L)","route":"/biomarkers/ar-ligand-binding-domain-mutation/"},{"id":"bcl2-g101v","kind":"biomarker","name":"BCL2 G101V and the other venetoclax binding-site mutations","route":"/biomarkers/bcl2-g101v/"},{"id":"btk-c481s","kind":"biomarker","name":"BTK resistance mutations: C481S, and 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/"}]}}