Lineage plasticity
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.
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 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.
What happens
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 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 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.
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.
- TarlatamabApprovedSmall-cell lung cancerExtensive-stage small-cell lung cancerLimited-stage small-cell lung cancer
- ObrixtamigPhase 3
- ZL-1310Phase 3
- DJI136Phase 2
- PeluntamigPhase 2
- Rovalpituzumab tesirineWithdrawn
- MevrometostatPhase 3
- XNW5004Phase 2
- TazemetostatWithdrawn
- AfatinibApprovedNon-small-cell lung cancerEGFR-mutated non-small-cell lung cancerHER2-mutant non-small-cell lung cancer
- AmivantamabApprovedNon-small-cell lung cancerEGFR-mutated non-small-cell lung cancerMET exon 14 and MET-amplified non-small-cell lung cancer
- AumolertinibApprovedNon-small-cell lung cancer
- CetuximabApprovedColorectal cancerHead and neck squamous cell carcinomaRecurrent or metastatic head and neck squamous cell carcinoma
- Cetuximab sarotalocanApprovedHead and neck squamous cell carcinoma
- cobas EGFR Mutation Test v2ApprovedNon-small-cell lung cancer
- DacomitinibApprovedNon-small-cell lung cancer
- EncorafenibApprovedColorectal cancerMelanomaNon-small-cell lung cancer
- +42 more at EGFR →
- Abiraterone acetateApprovedProstate cancerMetastatic hormone-sensitive prostate cancerMetastatic castration-resistant prostate cancer
- ApalutamideApprovedProstate cancerNon-metastatic castration-resistant prostate cancerMetastatic hormone-sensitive prostate cancer
- BicalutamideApprovedProstate cancerSalivary duct carcinoma
- DarolutamideApprovedProstate cancerNon-metastatic castration-resistant prostate cancerMetastatic hormone-sensitive prostate cancer
- DegarelixApprovedProstate cancer
- EnzalutamideApprovedProstate cancerSalivary duct carcinomaMetastatic hormone-sensitive prostate cancer
- FlutamideApprovedProstate cancer
- Leuprolide (leuprorelin) and GnRH agonistsApprovedProstate cancerHR-positive / HER2-negative breast cancerSalivary duct carcinoma
- +9 more at Androgen receptor →
- SelinexorApprovedEndometrial cancerMultiple myelomaDiffuse large B-cell lymphoma
- OSE2101Phase 3
- KRT-232Phase 2
- EprenetapoptNegative
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
- preclinical evidenceresearchDesign drug pairs where resisting one makes you vulnerable to the other
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.
- speculativeresearchDetect tumours changing cell type from RNA in the blood
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.
- 2022reviewHallmarks of Cancer 2022: adding phenotypic plasticity, epigenetic reprogramming, microbiomes and senescent cellsCancer Discovery
- 2020reviewImpact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung CancersMolecular cell
- 2017observationalRb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistanceScience
- 2011observationalGenotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitorsScience Translational Medicine
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.
- Can EZH2 inhibition prevent the switch if given early with AR or EGFR blockade?
- Can transformation be detected in blood before the biopsy shows it?
- 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 clinicalresearchGroup trials by broken mechanism, not by organ or single mutation
Rare cancers often share a broken cellular machine even when they arise in different organs. Grouping patients by that shared fault makes trials possible.
- early clinicalresearchUnmask hidden antigens with a short epigenetic course before immunotherapy
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.
- preclinical evidenceresearchBlock the chemical switch that lets cells hide from treatment
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.
- preclinical evidenceFocused-ultrasound BBB opening to deliver ADCs and radioligands to glioma
Brain tumours have targets that ADCs could hit, but antibodies cannot cross the barrier. Open the barrier with ultrasound first.
- preclinical evidenceresearchOpen the barrier so engineered immune cells can enter the brain
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.
- preclinical evidenceSubtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed)
Small-cell lung cancer is at least four diseases under the microscope's uniform appearance. Treat each by its transcription-factor subtype.
- speculativeAlpha radioligands after ADC failure
When ADCs against a surface protein stop working because the payload no longer kills, use the same protein to deliver radiation instead.
- speculativeclinicRe-map the tumour's surface proteins before choosing the next antibody drug
Antibody drugs need their target to still be present. After one fails, checking which surface markers remain would guide the choice of the next one instead of guessing.
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2023rctDeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancerNew England Journal of Medicinechanged practice
- 2022reviewHallmarks of Cancer 2022: adding phenotypic plasticity, epigenetic reprogramming, microbiomes and senescent cellsCancer Discovery
- 2020reviewImpact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung CancersMolecular cell
- 2017observationalRb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistanceScience
- 2011observationalGenotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitorsScience Translational Medicine
- 2004basicSingh 2004: identification of human brain tumour initiating cellsNature
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.