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.
Lineage plasticity requires loss of the gatekeepers TP53 and RB1 (Ku et al., Mu et al. 2017), which unlocks SOX2, EZH2-mediated repression of lineage genes, and reactivation of neural programmes (ASCL1, NEUROD1, INSM1, BRN2), producing AR-indifferent neuroendocrine prostate cancer in 15-20% of castration-resistant cases after potent AR inhibitors, and small-cell transformation in ~5-15% of EGFR-mutant NSCLC on osimertinib (also after ALK inhibitors and in immunotherapy-treated adenocarcinoma). Related transitions: squamous transdifferentiation of adenocarcinoma, sarcomatoid dedifferentiation in RCC and mesothelioma, MITF-low neural-crest states in melanoma under BRAF inhibitors, and blast/Richter transformation in lymphoid cancers. The new state expresses DLL3, SEZ6, B7-H3, CEACAM5 and loses PSMA or EGFR dependence, is transiently sensitive to platinum-etoposide, and is detected by biopsy at progression (recommended when PSA is low relative to disease burden or ctDNA shows TP53/RB1 loss) and by DLL3 PET. Therapeutics: DLL3 engagers (tarlatamab), EZH2 inhibitors (mevrometostat + enzalutamide, tazemetostat) to block or reverse the switch, Aurora A inhibitors for MYCN/ASCL1 states, and B7-H3 or SEZ6 ADCs.
In one picture
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.
Diagram
top- Re-biopsy at progression when the clinical picture and markers diverge; ctDNA TP53/RB1 loss as a warning
- DLL3 T-cell engager tarlatamab (SCLC; trials in neuroendocrine prostate cancer); B7-H3 and SEZ6 ADCs
- EZH2 inhibitors (mevrometostat with enzalutamide, tazemetostat) to prevent or reverse plasticity; Aurora A inhibitors for MYCN/ASCL1-high states
- Platinum-etoposide gives transient responses in transformed disease
Pages like this
not linked directly; found by shared links- PathwayDrug-tolerant persister cells
Shares EZH2, Cancer stem cells & phenotypic plasticity, Epigenetic reprogramming, Resistance routes: how a blocked pathway comes back and the tags mechanism, mechanics-atlas.
- PathwayTranscriptional machinery & addiction
Shares Enzalutamide, EZH2, Androgen receptor signalling, Epigenetic reprogramming and the tags mechanism, mechanics-atlas.
- PathwayCold tumours: immune deserts and exclusion
Shares Tazemetostat, EZH2, Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET), T-cell engagers (bispecific) and the tags mechanism, mechanics-atlas.
- PathwayDrug efflux pumps (ABC transporters)
Shares Cancer stem cells & phenotypic plasticity, Resistance routes: how a blocked pathway comes back, Acquired resistance to every therapy, Antibody-drug conjugate (ADC) and the tags mechanism, mechanics-atlas.
- PathwayThe blood–brain barrier & brain metastasis
Shares Osimertinib, Small-cell lung cancer, EGFR, Melanoma and the tags mechanism, mechanics-atlas.
- PathwayDrivers, passengers & the two-hit model
Shares p53 / RB / cell-cycle checkpoint, Osimertinib, TP53, EGFR and the tags mechanism, mechanics-atlas.
- PathwayThe cell-cycle engine (cyclins & CDKs)
Shares p53 / RB / cell-cycle checkpoint, TP53, Small-cell lung cancer and the tags mechanism, mechanics-atlas.
- PathwayReceptor tyrosine kinase activation
Shares Resistance routes: how a blocked pathway comes back, Osimertinib, EGFR, Antibody-drug conjugate (ADC) and the tags mechanism, mechanics-atlas.