Resistance routes: how a blocked pathway comes back
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.
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).
In one picture
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).
Diagram
top- 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
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