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Cancer cells can install pumps that throw chemotherapy back out. The same pumps guard gut, brain and marrow, which is why blocking them failed and why ADC designers now pick payloads the pumps cannot grip.
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 nightclub bouncer who throws out anyone in a particular jacket. Sacking the bouncer (P-gp inhibitors) also emptied the club of the staff who kept the place safe (gut, brain, marrow). The fix was to change jackets: payloads the bouncer does not recognise.
KEAP1-NRF2 is a smoke detector wired to a sprinkler system. Cancers jam the detector on, so the sprinklers run constantly and wash away every poison you throw at them.
In plain words, then the glossary entries the stage rests on. Chapter 9, Why treatments fail: Every cancer drug eventually meets resistance.
Cancer cells can install pumps that throw chemotherapy back out. The same pumps guard gut, brain and marrow, which is why blocking them failed and why ADC designers now pick payloads the pumps cannot grip.
Drug efflux pumps (ABC transporters). Cancer cells can install pumps in their outer membrane that throw chemotherapy back out as fast as it comes in. The same pumps guard the gut, brain and bone marrow in healthy tissue, which is why blocking them failed as a strategy and why drug designers now choose payloads the pumps cannot grip.
KEAP1-NRF2 antioxidant pathway. KEAP1-NRF2 is the cell's antioxidant defence switch. Lung cancers often break the off-switch (KEAP1), leaving NRF2 permanently on, which detoxifies chemotherapy and radiation and makes these tumours resistant to almost everything.
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-signal receptor. Some cancers make far too much of it, and drugs that block it or use it as a docking site have transformed those cancers.
TROP2 is a surface glycoprotein present at high levels on most epithelial cancers (breast, lung, urothelial, gastric, pancreatic) and at low levels on normal tissue. It does not drive the cancer; it is a delivery address, used by the approved ADCs sacituzumab govitecan and datopotamab deruxtecan and by sacituzumab tirumotecan, with a TROP2 PET tracer in development to pick patients.
KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021.
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.
About a third of triple-negative tumours are HER2-low and so eligible for trastuzumab deruxtecan, but the difference between a HER2 score of 0 and 1+ is the one pathologists agree on least, and most triple-negative tumours were scored before the label mattered. Re-scoring archived slides with digital help when a patient relapses would find the eligible third.
Group patients by why their last drug stopped working, then test the combination designed to fix that specific failure, whatever the cancer.
Some tumours pump out every drug. Use treatments the pumps cannot touch: radiation, radioligands, immune cells, and payloads designed to evade them.
Rather than waiting for resistance to one payload and then switching, give two mechanisms from day one, as HIV therapy does.
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.
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.
Record, for every patient, the order of treatments and what happened, so that the most common sequences can be compared and the worst ones flagged.
Stomach cancer now has three add-on biomarkers (HER2, PD-L1, Claudin 18.2) that often overlap. Test whether combining two add-ons beats picking one.
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.
Antibody-drug conjugates deliver chemotherapy payloads into tumours but cause lung, eye and nerve damage that tracks total exposure, and several were approved without an optimised dose. Randomised comparisons of lower doses, longer intervals and capped cumulative payload could keep the benefit while cutting these harms.
Serous endometrial cancers often overproduce HER2. Enhertu already works in them; testing HER2 in every p53-abnormal tumour and using the ADC earlier could change outcomes for the worst subtype.
Several drugs are approved for the same cancer, but nobody tests which order works best because no company benefits from the answer. Public multi-arm trials could settle these questions efficiently.
Antibody-drug conjugates built on the same linker and payload, such as deruxtecan or vedotin, share the same conjugation process, payload synthesis, impurity profile and much of the toxicology. FDA, EMA and PMDA should designate these linker-payloads as platforms so a new ADC files only antibody-specific manufacturing and toxicology data.
Between one in eleven and one in five gallbladder cancers is HER2-positive and two HER2 drugs are now approved, but testing still happens only when someone asks. Making it automatic on every advanced biliary diagnosis, on resection tissue where it exists, would find the patients the trials were built for.
Use a whole-body TROP2 scan instead of a single tissue stain to decide which patients get a TROP2 ADC, which one, and when to switch.
19 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 9.4 of 56.