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Five routes back when a pathway is blocked: mutate the target, make more of it, bypass, mutate downstream, or change identity. Plus the pharmacological escapes: pumps, sanctuaries, lost antigens.
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.
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).
Clonal evolution is like weeding a field with one herbicide year after year: the field fills with the one weed that shrugs it off. Rotating herbicides and leaving some susceptible weeds to crowd out the resistant ones is the evolutionary alternative.
In plain words, then the glossary entries the stage rests on. Chapter 9, Why treatments fail: Every cancer drug eventually meets resistance.
Five routes back when a pathway is blocked: mutate the target, make more of it, bypass, mutate downstream, or change identity. Plus the pharmacological escapes: pumps, sanctuaries, lost antigens.
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.
Clonal evolution & minimal residual disease. A tumour is a population that evolves by natural selection. Treatment kills the sensitive cells and selects the rest, which is why resistance is the rule; measuring the surviving population (MRD) and adapting therapy is the counter-strategy.
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 growth receptor that is mutated in some lung cancers and overproduced in others; the first great success of targeted pills.
A receptor that is either mutated in some lung cancers or amplified as an escape route when other lung cancer drugs fail.
The hormone switch that drives most breast cancers. Blocking or destroying it is the oldest and most effective targeted therapy.
The fusion that defines chronic myeloid leukaemia and a quarter of adult acute lymphoblastic leukaemia; the first cancer driver ever switched off by a pill.
The signalling enzyme that B-cell cancers use to survive. Blocking it turned chronic lymphocytic leukaemia into a disease controlled by a daily pill.
CD19 is a marker on B cells and B-cell cancers, and was the target of the first CAR-T therapies ever approved.
KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021.
PIK3CA is the most commonly mutated gene in hormone-driven breast cancer. Drugs against it work, but hitting it cleanly without raising blood sugar took years.
A protein that appears on the surface of small-cell lung cancer cells, now hit by a drug that pulls T cells onto them.
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.
The first drug against the KRAS protein nearly doubled survival in pancreatic cancer in 2026, but on its own it holds the disease for months, not years. Trials are now testing it in combination with a second RAS drug and with chemotherapy, and earlier in the disease; the open questions are which combination, in which order, and what works when the tumour escapes.
If most tumours escape a drug by the same back-up route, blocking that route from the start may prevent resistance rather than chase it.
Rather than giving the same dose until the cancer grows, measure tumour DNA in blood every few weeks and let a validated algorithm raise, lower, pause or switch drugs to keep the cancer suppressed for longer.
When a scan shows most tumours shrinking but one growing, that odd lesion holds the escape mechanism. Sampling it, and treating it locally, should be routine.
If destroying BTK works when every inhibitor has failed, using it first might stop resistance from ever emerging.
Adaptive therapy uses just enough drug to keep a tumour in check, pausing when the burden falls and resuming when it rises, so drug-sensitive cells suppress resistant ones. A prostate cancer pilot with abiraterone lengthened time to progression against historical controls on half the drug; randomised phase 2 trials are the next step.
When a treatment stops working, the tumour is rarely re-sampled, so nobody learns why. Paying for a biopsy at that moment would build the missing map of resistance.
When a targeted drug stops working, the tumour has usually changed in a way you can read. Most patients still move to the next treatment on a protocol rather than on a test of what actually happened.
Resistant cancer cells can become dependent on the drug they resisted, as shown for BRAF-inhibitor-resistant melanoma in mice. Stopping the drug for a defined washout and then rechallenging, while tracking the resistance allele in blood tumour DNA, could make the tumour vulnerable to it once more.
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.
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.
Several treatments now work without chemotherapy, but most are given until the disease comes back. Giving them for a fixed time and stopping is the version patients would choose.
Pack-year rules miss people who get lung cancer without heavy smoking, including East Asian women who never smoked, as Taiwan's TALENT study showed. Eligibility by a validated risk model with a set threshold, plus a never-smoker arm where family history matters, would find more cancers per scan.
Blood tests can already detect tumour DNA. Reporting which sub-populations of the tumour are growing or shrinking, cycle by cycle, would turn the test into an evolution monitor.
Three antibody-drug conjugates now used in triple-negative breast cancer carry the same kind of chemotherapy warhead, a topoisomerase inhibitor. Nobody has randomised which to give first or whether the second works after the first; small series suggest it often does not. With two now approved first line, the question decides what a patient gets for the rest of her life.
Whole regions of tissue carry cancer mutations long before a tumour exists. Detecting and treating the field, not the tumour, could prevent cancers rather than cure them.
A 5 mg tamoxifen dose halves breast cancer recurrence after precancer with far fewer side effects than the full dose. Almost nobody is prescribed it. Change who can prescribe.
SERENA-6 showed you can act on a blood test before the scan changes. The same logic could apply to PIK3CA, AKT1, or HER2 mutations emerging on treatment.
Cell therapies fail when the tumour stops showing the marker they were built to find. Preparing an alternative product in advance would let doctors switch quickly.
Metastatic prostate cancer now has six classes of treatment that work, and no trial has ever compared the orders they can be given in. Every trial adds a drug to the front; none asks what should follow it, so the sequence a man receives is decided by habit and by what was licensed first.
Treatment is often chosen from a biopsy taken years earlier from the original tumour. The spread disease may now look different. Test it again before switching drugs.
48 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 9.1 of 56.