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Of the 52 escape routes in the atlas, 35 have at least one countermeasure with clinical evidence, 17 have only preclinical or conceptual answers, and 0 have none recorded. The last two groups, listed here by drug class and linked to the ideas that target them, are where a drug designer should look.
Resistance can be to the address (antigen) or to the poison (payload). Payload resistance is shared across every TOP1 ADC regardless of target, which is why a second one often fails.
TOP1 mutations (e.g., E418K) or reduced expression prevent trapping of the cleavage complex.
Schlafen-11 is required for replication-stress-induced death; its epigenetic silencing confers resistance to TOP1 (and platinum) agents.
Reduced HER2 or TROP2 surface expression after treatment; less frequent than payload resistance for HER2-low disease.
Myeloma escapes BCMA drugs by deleting or mutating the target, or by exhausting the T cells that were supposed to do the killing.
Deletion or mutation removes or alters the epitope; more common after bispecifics than CAR-T.
Leukaemia and lymphoma relapse after CD19 CAR-T either without CD19 (the target is gone) or with it (the CAR-T cells are gone or exhausted).
Limited expansion or early loss of CAR-T cells; 4-1BB products persist longer than CD28.
PD-1 upregulation, TGF-β, and myeloid suppression in lymphoma.
Tumours that lost BRCA can regain repair by re-mutating BRCA back into working order, or by finding another way to protect their DNA.
Loss of end-protection factors lets BRCA1-deficient cells resect DNA ends and repair by HR.
Stabilised forks tolerate PARP trapping; PARP1 mutations abolish trapping.
Most patients never respond (primary resistance) and some responders relapse (acquired). The routes are loss of antigen presentation, no T cells in the tumour, and a suppressive microenvironment.
Mutations in B2M or HLA class I stop tumour cells displaying antigen; JAK1/2 loss removes interferon responsiveness (and PD-L1 induction).
Immunoediting removes the clones that carried immunogenic mutations.
Each ALK drug generation was beaten by a new mutation in the kinase; lorlatinib covers nearly all of them, so resistance now runs through other pathways.
Alternative receptors or downstream mutations re-activate MAPK/PI3K.
Prostate cancer keeps the androgen receptor working without hormones (amplification, splice variants), or abandons it and becomes a neuroendocrine cancer.
Truncated receptor lacking the ligand-binding domain is constitutively active and invisible to enzalutamide.
A bispecific needs the target on the tumour and a working T cell in the lymph node, so it is exposed to both failures at once: the antigen can go, and the patient's T cells can be worn out by the treatments that came before.
Suppressive myeloid cells, PD-L1 on the tumour and the stroma, and fibrosis can switch off a synapse the drug has successfully formed.
Hormone-positive breast cancer escapes either by mutating the oestrogen receptor so it no longer needs oestrogen, or by rewiring the cell-cycle engine (RB loss, cyclin E) so CDK4/6 no longer matters.
CCNE1 amplification or CDK2 activity bypasses the G1 block.
Lung cancers on osimertinib escape by mutating the drug's binding site, switching on a bypass receptor (MET), or changing cell type entirely.
Conversion to small-cell lung cancer (RB1/TP53 co-loss) or squamous histology; EGFR mutation persists but the cell no longer depends on it.
Blocking one RAS mutant makes the cell turn up every upstream receptor and often mutate KRAS again; that is why responses are short and why combinations and pan-RAS drugs followed.
Alternative MAPK activation.
A countermeasure counts as clinical when it cites a product that is approved or in phase 2 or later, or cites a trial. It counts as preclinical when it cites only preclinical or phase 1 products, technologies, terms or ideas. Ideas are linked when a countermeasure or the mechanism cites them, or when they name a target the mechanism names. The atlas is curated, so “none recorded” means OnCo has not recorded one, and a correction is welcome.