# Resistance routes: how a blocked pathway comes back

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

## TL;DR

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).

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- 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).
- 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

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Drug_resistance
- Vasan, Baselga & Hyman, A view on drug resistance in cancer (Nature 2019): https://doi.org/10.1038/s41586-019-1730-1

## Connected records

- cancers: [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Radioligand therapy (beta emitters)](https://onco.cc/technologies/radioligand-therapy/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [ALK](https://onco.cc/targets/alk/), [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [BCMA](https://onco.cc/targets/bcma/), [BCR::ABL1 (Philadelphia chromosome)](https://onco.cc/targets/bcr-abl/), [BTK (Bruton tyrosine kinase)](https://onco.cc/targets/btk/), [CD19](https://onco.cc/targets/cd19/), [DLL3](https://onco.cc/targets/dll3/), [EGFR](https://onco.cc/targets/egfr/), [Estrogen receptor (ERα)](https://onco.cc/targets/estrogen-receptor/), [FAK (PTK2)](https://onco.cc/targets/fak/), [HER3](https://onco.cc/targets/her3/), [KRAS](https://onco.cc/targets/kras/), [MET](https://onco.cc/targets/met/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [RB1](https://onco.cc/targets/rb1/), [SHP2 (PTPN11)](https://onco.cc/targets/shp2/)
- drugs: [Amivantamab](https://onco.cc/drugs/amivantamab/), [Asciminib](https://onco.cc/drugs/asciminib/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [Elacestrant](https://onco.cc/drugs/elacestrant/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/), [Osimertinib](https://onco.cc/drugs/osimertinib/), [Pirtobrutinib](https://onco.cc/drugs/pirtobrutinib/), [Sotorasib](https://onco.cc/drugs/sotorasib/), [Tarlatamab](https://onco.cc/drugs/tarlatamab/)
- pathways: [Antigen presentation & immune editing](https://onco.cc/pathways/antigen-presentation-immunoediting/), [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/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Antigen escape: how a lymphoma loses the thing the drug was aimed at](https://onco.cc/terms/lymphoma-bio-antigen-escape/), [AR-V7 splice variant](https://onco.cc/terms/ar-v7/), [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/), [Drug efflux pumps (ABC transporters)](https://onco.cc/terms/efflux-pump/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [EGFR C797S](https://onco.cc/terms/c797s/), [ESR1 mutation](https://onco.cc/terms/esr1-mutation/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [MET amplification (bypass resistance)](https://onco.cc/terms/met-amplification/), [Oligoprogression](https://onco.cc/terms/oligoprogression/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- key papers: [A view on drug resistance in cancer](https://onco.cc/key-papers/paper-vasan-nature/), [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/), [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/), [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/), [Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer](https://onco.cc/key-papers/paper-misale-kras-acquired-resistance-anti-egfr-colorectal-nature-2012/), [Genomic analysis of circulating tumour DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms](https://onco.cc/key-papers/paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021/), [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/), [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/), [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/), [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/), [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/)
- 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/)

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