Efflux pumps
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.
Diagram
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.
What happens
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 molecular players
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.
Where medicines act
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.
- Trastuzumab deruxtecanApprovedHER2-positive breast cancerHR-positive / HER2-negative breast cancerGastric & gastro-oesophageal junction cancer
- AfatinibApprovedNon-small-cell lung cancerEGFR-mutated non-small-cell lung cancerHER2-mutant non-small-cell lung cancer
- Disitamab vedotinApprovedGastric & gastro-oesophageal junction cancerBladder & urothelial cancer
- HER2 IHC and ISH companion assays (HercepTest, PATHWAY 4B5, HER2 Dual ISH)ApprovedHER2-positive breast cancerHR-positive / HER2-negative breast cancerGastric & gastro-oesophageal junction cancer
- InetetamabApprovedHER2-positive breast cancer
- LapatinibApprovedHER2-positive breast cancerHER2-positive breast cancer with brain metastases
- MargetuximabApprovedHER2-positive breast cancer
- NeratinibApprovedHER2-positive breast cancerHER2-positive breast cancer with brain metastases
- +35 more at HER2 →
- Datopotamab deruxtecanApprovedTriple-negative breast cancer (TNBC)HR-positive / HER2-negative breast cancerNon-small-cell lung cancer
- Sacituzumab govitecanApprovedTriple-negative breast cancer (TNBC)HR-positive / HER2-negative breast cancerBladder & urothelial cancer
- Sacituzumab tirumotecanApprovedTriple-negative breast cancer (TNBC)Non-small-cell lung cancerHR-positive / HER2-negative breast cancer
- BIO-106Phase 2
- EB-NK-301Phase 2
- LCB84Phase 2
- AK146D1Phase 1
- AdagrasibApprovedNon-small-cell lung cancerColorectal cancerPancreatic ductal adenocarcinoma
- Avutometinib + defactinibApprovedOvarian cancerLow-grade serous ovarian cancer
- DaraxonrasibApprovedPancreatic ductal adenocarcinomaMetastatic pancreatic ductal adenocarcinomaKRAS G12C-mutant pancreatic ductal adenocarcinoma
- FulzerasibApprovedNon-small-cell lung cancer
- GarsorasibApprovedNon-small-cell lung cancerKRAS G12C-mutant non-small-cell lung cancer
- GlecirasibApprovedNon-small-cell lung cancerKRAS G12C-mutant non-small-cell lung cancer
- Guardant360 CDxApprovedNon-small-cell lung cancerHR-positive / HER2-negative breast cancer
- Resolution ctDx FIRSTApprovedNon-small-cell lung cancer
- +16 more at KRAS →
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
- preclinical evidenceresearchCombination baskets defined by resistance mechanism rather than by cancer type
Group patients by why their last drug stopped working, then test the combination designed to fix that specific failure, whatever the cancer.
- preclinical evidenceEfflux-agnostic therapy for mesenchymal TNBC
Some tumours pump out every drug. Use treatments the pumps cannot touch: radiation, radioligands, immune cells, and payloads designed to evade them.
- speculativeDual-payload ADCs in first line to prevent resistance
Rather than waiting for resistance to one payload and then switching, give two mechanisms from day one, as HIV therapy does.
- 2019rctKATHERINE: switching to T-DM1 when HER2-positive breast cancer survives pre-surgery treatmentNew England Journal of Medicinechanged practice
- 2018reviewRevisiting the role of ABC transporters in multidrug-resistant cancerNature Reviews Cancer
- 1987translationalSlamon 1987: HER2 gene amplification marks an aggressive form of breast cancerSciencechanged practice
Measured by
Biomarkers, tests and assays in the corpus that read this stage in a patient.
Open questions
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.
- Which payload should follow which after an ADC fails: is efflux the reason for cross-resistance?
- Can pump expression be measured on a biopsy to guide payload choice?
- early clinicaldataA registry of every treatment sequence patients actually receive, with outcomes
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.
- early clinicalBiomarker-directed first-line quadruplets in gastric cancer
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.
- early clinicalclinicDeliver CAR-T cells straight into the fluid around the brain
Cancer spreading along the linings of the brain is almost untreatable. Injecting engineered immune cells directly into the brain fluid, through a small reservoir, reaches it.
- early clinicalindustryDose and schedule optimisation trials specific to antibody-drug conjugates
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.
- early clinicalHER2 ADCs as standard for HER2-positive serous endometrial cancer
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.
- early clinicalresearchMulti-arm, multi-stage trials to answer which order to give approved drugs
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.
- early clinicalregulatorPlatform designation for ADC linker-payloads so manufacturing data carry across
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.
- early clinicalTROP2 PET to choose and sequence TROP2 ADCs
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.
- preclinical evidenceindustryBispecific antibodies that engage macrophages instead of T cells
Drugs that grab T cells and drag them onto tumours work well in blood cancers. The same trick aimed at tumour-eating cells might work where T cells are absent.
- preclinical evidenceengineeringContinuous-flow synthesis of ultra-potent ADC payloads to ease the capacity squeeze
The poisons carried by antibody-drug conjugates are so toxic that only a few factories can make them, and they are booked years ahead. Making them in small continuous reactors would ease the bottleneck.
17 more ideas are linked to this stage's pathways, targets and terms; see the rankings →
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2024rctDESTINY-Breast06: trastuzumab deruxtecan before any chemotherapy in hormone-receptor-positive, HER2-low or ultralow breast cancerNew England Journal of Medicinechanged practice
- 2024rctEV-302: enfortumab vedotin plus pembrolizumab replaces chemotherapy as first treatment for advanced bladder cancerNew England Journal of Medicinechanged practice
- 2024rctTROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survivalJournal of Clinical Oncology
- 2022rctDESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancerNew England Journal of Medicinechanged practice
- 2022rctDESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable groupNew England Journal of Medicinechanged practice
- 2021rctASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancerNew England Journal of Medicinechanged practice
- 2019rctKATHERINE: switching to T-DM1 when HER2-positive breast cancer survives pre-surgery treatmentNew England Journal of Medicinechanged practice
- 2018reviewRevisiting the role of ABC transporters in multidrug-resistant cancerNature Reviews Cancer
- 2017basicKeap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysisNature Medicine
- 2010reviewLemmon and Schlessinger 2010: cell signalling by receptor tyrosine kinasesCell
- 2010rctToGA (Bang 2010): trastuzumab with chemotherapy for HER2-positive advanced gastric cancerThe Lancetchanged practice
- 2001rctSlamon 2001: adding trastuzumab to chemotherapy for HER2-positive metastatic breast cancerNew England Journal of Medicinechanged practice
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.