{"entity":{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","aka":[],"tldr":"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.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor","links":[{"label":"Ku et al., Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance (Science 2017)","url":"https://doi.org/10.1126/science.aah4199"},{"label":"Beltran et al., Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer (Nat Med 2016)","url":"https://doi.org/10.1038/nm.4045"}],"tags":["mechanism","mechanics-atlas"],"related":[],"indications":["prostate","sclc"],"sections":[],"technologies":[],"targets":["dll3","b7h3","ceacam5","psma"],"drugs":["enzalutamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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.","nodes":[{"id":"adeno","label":"Adenocarcinoma (AR / EGFR)","x":12,"y":15},{"id":"drug","label":"ARPI or EGFR TKI pressure","x":12,"y":48},{"id":"loss","label":"TP53 + RB1 loss","x":45,"y":15},{"id":"sox2","label":"SOX2, EZH2, ASCL1/NEUROD1","x":45,"y":48},{"id":"ne","label":"Neuroendocrine / small-cell","x":78,"y":30},{"id":"dll3","label":"DLL3, B7-H3, SEZ6 surface","x":78,"y":62,"targetId":"dll3"},{"id":"indiff","label":"AR / EGFR indifferent","x":45,"y":82},{"id":"tx","label":"Tarlatamab, platinum-etoposide","x":78,"y":92},{"id":"ezh2i","label":"EZH2 inhibitors block switch","x":12,"y":82}],"edges":[{"from":"adeno","to":"ne","type":"activates"},{"from":"drug","to":"sox2","type":"activates"},{"from":"loss","to":"sox2","type":"activates"},{"from":"sox2","to":"ne","type":"activates"},{"from":"ne","to":"dll3","type":"activates"},{"from":"ne","to":"indiff","type":"activates"},{"from":"drug","to":"adeno","type":"inhibits"},{"from":"tx","to":"ne","type":"inhibits"},{"from":"ezh2i","to":"sox2","type":"inhibits"}],"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"]},"route":"/pathways/lineage-plasticity-neuroendocrine/","neighbours":{"indication":[{"id":"prostate","kind":"indication","name":"Prostate cancer","route":"/indications/prostate/"},{"id":"sclc","kind":"indication","name":"Small-cell lung cancer","route":"/indications/sclc/"}],"target":[{"id":"b7h3","kind":"target","name":"B7-H3","route":"/targets/b7h3/"},{"id":"ceacam5","kind":"target","name":"CEACAM5","route":"/targets/ceacam5/"},{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"},{"id":"psma","kind":"target","name":"PSMA","route":"/targets/psma/"}],"drug":[{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"}],"pathway":[{"id":"prostate-cancer-signalling","kind":"pathway","name":"Prostate cancer (KEGG map)","route":"/pathways/prostate-cancer-signalling/"}]}}