Unaddressed resistance routes

Of the 38 escape routes in the atlas, 22 have at least one countermeasure with clinical evidence, 16 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.

Topoisomerase-I payload ADCs

0 none3 preclinicalof 5

BCMA-directed therapy

0 none2 preclinicalof 3

CD19 CAR-T

0 none2 preclinicalof 3

PARP inhibitors

0 none2 preclinicalof 4

PD-1 / PD-L1 checkpoint inhibitors

0 none2 preclinicalof 5

ALK tyrosine kinase inhibitors

0 none1 preclinicalof 2

Androgen receptor pathway inhibitors

0 none1 preclinicalof 5

CDK4/6 inhibitor + endocrine therapy

0 none1 preclinicalof 4

EGFR tyrosine kinase inhibitors

0 none1 preclinicalof 4

KRAS G12C inhibitors

0 none1 preclinicalof 3

Gaps by kind of escapeOn-target 2Bypass 4Lineage switch 1Payload 2Antigen loss 3Immune evasion 2Pharmacology 2

Drug class · 3 unaddressed of 5

Topoisomerase-I payload ADCs (T-DXd, sacituzumab govitecan, Dato-DXd)

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.

Payload · Topoisomerase-I payload ADCs

Payload resistance: TOP1 mutation or loss

TOP1 mutations (e.g., E418K) or reduced expression prevent trapping of the cleavage complex.

Topoisomerase-I inhibitors (and ADC payloads)ADC sequencing

Preclinical or conceptual only · 2

Switch payload class (tubulin, DNA-crosslinking, degrader) rather than antigen
Payload-class switching as the rule for ADC sequencing Dual-payload ADC
Radioconjugates against the same antigen
Alpha radioligands after ADC failure Radio-antibody & radio-ADC

Ideas that attack it · 2

Alpha radioligands after ADC failure Payload-class switching as the rule for ADC sequencing

Payload · Topoisomerase-I payload ADCs

SLFN11 loss

Schlafen-11 is required for replication-stress-induced death; its epigenetic silencing confers resistance to TOP1 (and platinum) agents.

Topoisomerase-I inhibitors (and ADC payloads)

Preclinical or conceptual only · 2

ATR/CHK1 inhibitors re-sensitise SLFN11-low cells preclinically
ATR
EZH2 inhibition to restore SLFN11 (preclinical)
EZH2

Antigen loss · Topoisomerase-I payload ADCs

Antigen loss or downregulation

Reduced HER2 or TROP2 surface expression after treatment; less frequent than payload resistance for HER2-low disease.

HER2 TROP2

Preclinical or conceptual only · 2

Antigen PET to detect loss and pick the next target
TROP2 PET HER2 PET TROP2 PET to choose and sequence TROP2 ADCs
Bispecific ADCs hitting two antigens
Bispecific ADC

Ideas that attack it · 11

Alpha radioligands after ADC failure An abbreviated approval path for follow-on antibodies within a validated class Biomarker-directed first-line quadruplets in gastric cancer Bispecific antibodies that engage macrophages instead of T cells Deliver CAR-T cells straight into the fluid around the brain Dual-payload ADCs in first line to prevent resistance HER2 ADCs as standard for HER2-positive serous endometrial cancer Re-map the tumour's surface proteins before choosing the next antibody drug

Drug class · 2 unaddressed of 3

BCMA-directed therapy (CAR-T, bispecifics, ADC)

Myeloma escapes BCMA drugs by deleting or mutating the target, or by exhausting the T cells that were supposed to do the killing.

Antigen loss · BCMA-directed therapy

BCMA antigen loss (biallelic TNFRSF17 deletion, extracellular mutations)

Frequency: ~10–30% after bispecifics

Deletion or mutation removes or alters the epitope; more common after bispecifics than CAR-T.

BCMA

Preclinical or conceptual only · 1

Switch to GPRC5D-directed therapy (talquetamab, GPRC5D CAR-T) or FcRH5
GPRC5D

Ideas that attack it · 5

Hospital-based CAR-T manufacturing at cost through a public network Hospital-made CAR-T under one shared regulatory master file In vivo CAR-T manufactured and priced like a generic biologic Non-profit, open-licence lentiviral vectors and producer cell lines for CAR-T Plan the second CAR-T target before the first one is lost

Pharmacology · BCMA-directed therapy

Soluble BCMA decoy

Shed BCMA binds drug in circulation.

BCMA

Preclinical or conceptual only · 1

Gamma-secretase inhibitors to reduce shedding (trials)
BCMA

Ideas that attack it · 5

Drug class · 2 unaddressed of 3

CD19 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).

Pharmacology · CD19 CAR-T

CD19-positive relapse from poor CAR-T persistence

Limited expansion or early loss of CAR-T cells; 4-1BB products persist longer than CD28.

CAR-T cell therapy

Preclinical or conceptual only · 1

Allogeneic or in vivo re-dosing; armoured CARs
In vivo CAR-T Allogeneic (off-the-shelf) cell therapy Armoured, logic-gated & next-gen CARs

Immune evasion · CD19 CAR-T

Immunosuppressive microenvironment and T-cell exhaustion

PD-1 upregulation, TGF-β, and myeloid suppression in lymphoma.

PD-1 / PD-L1 immune checkpoint & T-cell activation

Preclinical or conceptual only · 1

PD-1 knockout or blockade with CAR-T (trials)
Immune checkpoint inhibitors

Drug class · 2 unaddressed of 4

PARP inhibitors

Tumours that lost BRCA can regain repair by re-mutating BRCA back into working order, or by finding another way to protect their DNA.

Bypass · PARP inhibitors

Restoration of HR via 53BP1/Shieldin loss

Loss of end-protection factors lets BRCA1-deficient cells resect DNA ends and repair by HR.

DNA damage response & homologous recombination

Preclinical or conceptual only · 1

ATR inhibitors; POLQ inhibitors (trials)
ATR Synthetic lethality approaches

On-target · PARP inhibitors

Replication fork protection and PARP1 loss

Stabilised forks tolerate PARP trapping; PARP1 mutations abolish trapping.

PARP

Preclinical or conceptual only · 1

PARP1-selective saruparib for a wider window; PARP PET to confirm target
PARP PET

Ideas that attack it · 4

A functional test for homologous recombination deficiency validated across laboratories A synthetic lethality map for every cancer driver in every tissue context Subtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed)Which patients' blood clones will become leukaemia after treatment?

Drug class · 2 unaddressed of 5

PD-1 / PD-L1 checkpoint inhibitors

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.

Immune evasion · PD-1 / PD-L1 checkpoint inhibitors

Loss of antigen presentation (B2M, HLA, JAK1/2)

Frequency: Acquired resistance in melanoma: ~25% JAK/B2M

Mutations in B2M or HLA class I stop tumour cells displaying antigen; JAK1/2 loss removes interferon responsiveness (and PD-L1 induction).

PD-1 / PD-L1 immune checkpoint & T-cell activation

Preclinical or conceptual only · 1

NK-cell and CAR-based approaches that do not need MHC; T-cell engagers
CAR-NK & CAR-macrophage T-cell engagers (bispecific)

Antigen loss · PD-1 / PD-L1 checkpoint inhibitors

Loss of neoantigens / low TMB

Immunoediting removes the clones that carried immunogenic mutations.

Neoantigen Tumour mutational burden (TMB)

Preclinical or conceptual only · 1

Vaccines against shared antigens (KRAS)
Off-the-shelf cancer vaccines

Drug class · 1 unaddressed of 2

ALK tyrosine kinase inhibitors

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.

Bypass · ALK tyrosine kinase inhibitors

Bypass signalling (MET, EGFR, KRAS)

Alternative receptors or downstream mutations re-activate MAPK/PI3K.

MET KRAS

Preclinical or conceptual only · 1

Combination with MET or MEK inhibitors (trials); chemotherapy; ADCs
Small-molecule kinase inhibitors

Ideas that attack it · 16

A guaranteed purchase prize for the first drug against a named hard target A synthetic lethality map for every cancer driver in every tissue context Add a drug when the blood test turns, without stopping the one that works Add the second drug on day one when the escape route is predictable An open degrader consortium against every undruggable driver transcription factor An open-science consortium on the undruggable drivers, open until a candidate Antibodies that see mutant KRAS and p53 fragments displayed on the cell surface Block the survival signals the tumour's neighbours provide

Drug class · 1 unaddressed of 5

Androgen receptor pathway inhibitors (abiraterone, enzalutamide)

Prostate cancer keeps the androgen receptor working without hormones (amplification, splice variants), or abandons it and becomes a neuroendocrine cancer.

On-target · Androgen receptor pathway inhibitors

AR splice variants (AR-V7)

Truncated receptor lacking the ligand-binding domain is constitutively active and invisible to enzalutamide.

Androgen receptor

Preclinical or conceptual only · 1

Taxanes retain activity; N-terminal-domain inhibitors
Cytotoxic chemotherapy

Ideas that attack it · 1

Destroy the truncated androgen receptor that hormone drugs cannot touch

Drug class · 1 unaddressed of 4

CDK4/6 inhibitor + endocrine therapy

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.

Bypass · CDK4/6 inhibitor + endocrine therapy

Cyclin E / CDK2 activation

CCNE1 amplification or CDK2 activity bypasses the G1 block.

CDK4/6

Preclinical or conceptual only · 1

CDK2 inhibitors (AVZO-021 and others) and CDK4-selective inhibitors in trials
Avenzo Therapeutics

Ideas that attack it · 2

Attack extrachromosomal DNA, the engine of oncogene amplification CDK4-selective inhibitors as the new first-line backbone

Drug class · 1 unaddressed of 4

EGFR tyrosine kinase inhibitors (osimertinib)

Lung cancers on osimertinib escape by mutating the drug's binding site, switching on a bypass receptor (MET), or changing cell type entirely.

Lineage switch · EGFR tyrosine kinase inhibitors

Histologic transformation

Frequency: ~5–15%

Conversion to small-cell lung cancer (RB1/TP53 co-loss) or squamous histology; EGFR mutation persists but the cell no longer depends on it.

Small-cell lung cancer TP53

Preclinical or conceptual only · 1

Re-biopsy at progression; platinum-etoposide for SCLC transformation
Cytotoxic chemotherapy

Ideas that attack it · 19

A biomarker-directed trial of vitamin D after surgery for digestive tract cancers A guaranteed purchase prize for the first drug against a named hard target A synthetic lethality map for every cancer driver in every tissue context An open degrader consortium against every undruggable driver transcription factor An open-science consortium on the undruggable drivers, open until a candidate Antibodies that see mutant KRAS and p53 fragments displayed on the cell surface Degrade the damaged p53 protein rather than trying to repair it Detect tumours changing cell type from RNA in the blood

Drug class · 1 unaddressed of 3

KRAS G12C inhibitors

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.

Bypass · KRAS G12C inhibitors

Bypass alterations (MET amplification, NRAS/BRAF mutations, RTK fusions)

Alternative MAPK activation.

MET BRAF

Preclinical or conceptual only · 1

Combination with MEK/ERK inhibitors; re-biopsy-guided therapy
Small-molecule kinase inhibitors

Ideas that attack it · 10

A standard for tumour-agnostic approvals: minimum histologies and hierarchical modelling Add a drug when the blood test turns, without stopping the one that works Add the second drug on day one when the escape route is predictable Adopt tumour-agnostic cancer drug labels across regions by reliance, not re-review Block the survival signals the tumour's neighbours provide BRAF/MEK plus PD-1 blockade as standard for BRAF-mutant anaplastic thyroid cancer Design drug pairs where resisting one makes you vulnerable to the other Kill drug-tolerant persisters through ferroptosis

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.