# Lineage plasticity & neuroendocrine transformation

Source: https://nuclide.cc/pathways/lineage-plasticity-neuroendocrine/  
Nuclide record `lineage-plasticity-neuroendocrine` (Pathway). Data CC BY-NC 4.0, attribute "Data from Nuclide (nuclide.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- Analogy: 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.
- Interventions: 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

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Neuroendocrine_tumor
- Ku et al., Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance (Science 2017): https://doi.org/10.1126/science.aah4199
- Beltran et al., Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer (Nat Med 2016): https://doi.org/10.1038/nm.4045

## Connected records

- indications: [Prostate cancer](https://nuclide.cc/indications/prostate/), [Small-cell lung cancer](https://nuclide.cc/indications/sclc/)
- targets: [B7-H3](https://nuclide.cc/targets/b7h3/), [CEACAM5](https://nuclide.cc/targets/ceacam5/), [DLL3](https://nuclide.cc/targets/dll3/), [PSMA](https://nuclide.cc/targets/psma/)
- drugs: [Enzalutamide](https://nuclide.cc/drugs/enzalutamide/)
- pathways: [Prostate cancer (KEGG map)](https://nuclide.cc/pathways/prostate-cancer-signalling/)

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