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Under a drug that blocks its identity, a tumour can become a different kind of cell, most dramatically a small-cell neuroendocrine cancer that no longer needs the blocked signal. Not a new mutation in the engine: a new engine.
Pick a product above a diagram to see the nodes it hits and the escape routes below the block. Hover or tap any node or arrow for what it is; every node opens its target, glossary entry or the pathway page. Violet boxes are druggable targets.
A shop that sells hats is fined every time it sells a hat (AR blockade). One day it reopens as a bakery. The fine no longer applies, the old inspectors (PSA, PSMA scans) see nothing, and only a new set of tools works against the new business.
A weed that can turn from leaf to root to seed depending on what you spray on it. Kill the leaves and the roots wait; kill the roots and a seed reawakens.
In plain words, then the glossary entries the stage rests on. Chapter 9, Why treatments fail: Every cancer drug eventually meets resistance.
Under a drug that blocks its identity, a tumour can become a different kind of cell, most dramatically a small-cell neuroendocrine cancer that no longer needs the blocked signal. Not a new mutation in the engine: a new engine.
Lineage plasticity & neuroendocrine transformation. Under pressure from a drug that blocks its identity (the androgen receptor in prostate cancer, EGFR in lung cancer), a tumour can change what kind of cell it is, becoming a small-cell neuroendocrine cancer that no longer needs the blocked signal. It is the ultimate escape: not a new mutation in the engine, but a new engine.
Cancer stem cells & phenotypic plasticity. Some cancer cells behave like stem cells: they can regrow the whole tumour, resist treatment, and switch identities. This plasticity explains why tumours come back and why some lung and prostate cancers transform into a different cancer type under therapy.
The proteins and genes at this stage, with their role and how many products act on each. Listed players come from the atlas; drawn players sit as nodes in the diagrams above.
A protein that appears on the surface of small-cell lung cancer cells, now hit by a drug that pulls T cells onto them.
B7-H3 is an immune checkpoint-like surface protein found on 60 to 70% of small-cell lung cancers and 80 to 90% of castration-resistant prostate cancers, with little on normal tissue. It is used as an ADC address, chiefly by ifinatamab deruxtecan, now in phase 3 in small-cell lung cancer; whether blocking its immune-dampening role adds anything beyond payload delivery is unresolved.
EZH2 is an enzyme that silences genes. The first drug against it treated a rare sarcoma and some lymphomas until it was withdrawn in 2026 for causing second blood cancers.
A growth receptor that is mutated in some lung cancers and overproduced in others; the first great success of targeted pills.
The hormone switch that drives prostate cancer, attacked by castration and by pills that block the receptor.
TP53 is the 'guardian of the genome', broken in half of all cancers. Fixing it directly has so far defeated every attempt, so drugs exploit what its loss makes cancers depend on.
Products grouped by the node they hit, most advanced first, with the cancers an approved product is linked to. Pick one above the diagram to see it light up.
Records tied to this stage that describe resistance, evasion or tolerance. Resistance: how tumours escape each drug class lists the routes class by class.
Giving men with castration-resistant prostate cancer large doses of the hormone the treatment has spent years removing makes a third of them respond, and makes half of them respond again to the drug that had stopped working. It has never been taken to a definitive trial, partly because the endpoint that shows the benefit is not the one trials usually use.
Choose two treatments so that whatever the tumour does to escape the first, it becomes easier to kill with the second. The immune system is a good candidate partner.
In a minority of men, prostate cancer escapes hormone drugs by becoming a different kind of cell that no longer needs the androgen receptor. By the time a biopsy shows it, the treatment options are almost gone. The genetic changes that allow the switch are detectable years earlier, and nobody is looking for them.
Some cancers escape treatment by changing into a different kind of cell that the drug no longer affects. Tumour RNA in blood could show this shift months before a biopsy would.
Biomarkers, tests and assays in the corpus that read this stage in a patient.
What is not known at this stage: the atlas's own questions, the bottlenecks it bears on, and the ideas in the corpus that try to answer them.
Cancer spreading along the linings of the brain has no treatment that reliably controls it. Injecting engineered immune cells directly into the brain fluid, through a small reservoir, reaches it.
Rare cancers often share a broken cellular machine even when they arise in different organs. Grouping patients by that shared fault makes trials possible.
Low doses of drugs that change how DNA is packaged can make cancer cells display more of what marks them as abnormal, potentially waking up immunotherapy in cold tumours.
Three genetic classifications of the commonest aggressive lymphoma exist and none of them yet decides anyone's treatment. The trial that would change that has not been run.
Cells that survive treatment do so by changing which genes they use, not their DNA. Drugs that block that change may stop survivors from forming at all.
Brain tumours have targets that ADCs could hit, but antibodies cannot cross the barrier. Open the barrier with ultrasound first.
Engineered immune cells given by drip rarely reach brain tumours. Briefly opening the barrier with focused ultrasound at the right moment may let them in.
Small-cell lung cancer has had two real advances in twenty-five years. It is probably four diseases being tested as one, in separate small trials that each need their own control group.
Small-cell lung cancer is at least four diseases under the microscope's uniform appearance. Treat each by its transcription-factor subtype.
When ADCs against a surface protein stop working because the payload no longer kills, use the same protein to deliver radiation instead.
1 more ideas are linked to this stage's pathways, targets and terms; see the rankings →
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
src/data/mechanics-atlas.ts). Players, medicines, escape routes, tests, ideas and papers are resolved from the knowledge graph at build time through the stage's pathways, targets and terms, so every item here has its own page and sources. Where a section is missing, the corpus has no record tied to the stage yet. Nothing here is medical advice; see about and methodology. Stage 9.5 of 56.