{"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":[],"cancers":["prostate","nsclc","sclc","melanoma"],"sections":[],"technologies":["t-cell-engager","adc","epigenetic-drugs","liquid-biopsy","histopathology-ihc"],"targets":["dll3","b7h3","ezh2","tp53","androgen-receptor","egfr","ceacam5","psma"],"drugs":["tarlatamab","ifinatamab-deruxtecan","mevrometostat","tazemetostat","platinum-etoposide","enzalutamide","osimertinib"],"companies":[],"institutions":[],"pathways":["cancer-stem-cells-plasticity","ar-signaling","epigenetic-reprogramming","notch","p53-cell-cycle","resistance-routes-map"],"terms":["histologic-transformation","castration-resistance","unlocking-phenotypic-plasticity","richter-transformation","epithelioid-vs-sarcomatoid"],"trials":[],"people":[],"bottlenecks":["b-resistance"],"keyPapers":["paper-ku-rb1-trp53-lineage-plasticity-science-2017"],"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,"targetId":"androgen-receptor"},{"id":"drug","label":"ARPI or EGFR TKI pressure","x":12,"y":48,"targetId":"egfr"},{"id":"loss","label":"TP53 + RB1 loss","x":45,"y":15,"targetId":"tp53"},{"id":"sox2","label":"SOX2, EZH2, ASCL1/NEUROD1","x":45,"y":48,"targetId":"ezh2"},{"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":{"cancer":[{"id":"extrapulmonary-nec","kind":"cancer","name":"Extrapulmonary neuroendocrine carcinoma","route":"/cancers/extrapulmonary-nec/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"},{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"t-cell-engager","kind":"technology","name":"T-cell engagers (bispecific)","route":"/technologies/t-cell-engager/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"ascl1","kind":"target","name":"ASCL1","route":"/targets/ascl1/"},{"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":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"psma","kind":"target","name":"PSMA","route":"/targets/psma/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"sox2","kind":"target","name":"SOX2","route":"/targets/sox2/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"},{"id":"yap1","kind":"target","name":"YAP1","route":"/targets/yap1/"}],"drug":[{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"},{"id":"ifinatamab-deruxtecan","kind":"drug","name":"Ifinatamab deruxtecan","route":"/drugs/ifinatamab-deruxtecan/"},{"id":"mevrometostat","kind":"drug","name":"Mevrometostat","route":"/drugs/mevrometostat/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"platinum-etoposide","kind":"drug","name":"Platinum + etoposide (EP / CE)","route":"/drugs/platinum-etoposide/"},{"id":"tarlatamab","kind":"drug","name":"Tarlatamab","route":"/drugs/tarlatamab/"},{"id":"tazemetostat","kind":"drug","name":"Tazemetostat","route":"/drugs/tazemetostat/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"cancer-stem-cells-plasticity","kind":"pathway","name":"Cancer stem cells & phenotypic plasticity","route":"/pathways/cancer-stem-cells-plasticity/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"notch","kind":"pathway","name":"Notch signalling","route":"/pathways/notch/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"prostate-cancer-signalling","kind":"pathway","name":"Prostate cancer (KEGG map)","route":"/pathways/prostate-cancer-signalling/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"},{"id":"sclc-signalling","kind":"pathway","name":"Small cell lung cancer (KEGG map)","route":"/pathways/sclc-signalling/"}],"term":[{"id":"cancer-stem-cell-theory","kind":"term","name":"Cancer stem cell theory and phenotypic plasticity","route":"/terms/cancer-stem-cell-theory/"},{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"epithelioid-vs-sarcomatoid","kind":"term","name":"Epithelioid vs sarcomatoid (biphasic) mesothelioma","route":"/terms/epithelioid-vs-sarcomatoid/"},{"id":"unlocking-phenotypic-plasticity","kind":"term","name":"Hallmark (2022): unlocking phenotypic plasticity","route":"/terms/unlocking-phenotypic-plasticity/"},{"id":"histologic-transformation","kind":"term","name":"Histologic transformation","route":"/terms/histologic-transformation/"},{"id":"neuroendocrine-differentiation","kind":"term","name":"Neuroendocrine differentiation in prostate cancer","route":"/terms/neuroendocrine-differentiation/"},{"id":"richter-transformation","kind":"term","name":"Richter transformation","route":"/terms/richter-transformation/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"}],"paper":[{"id":"paper-yu-acquired-resistance-rebiopsy-egfr-ccr-2013","kind":"paper","name":"Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers","route":"/key-papers/paper-yu-acquired-resistance-rebiopsy-egfr-ccr-2013/"},{"id":"paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017","kind":"paper","name":"Androgen receptor pathway-independent prostate cancer is sustained through FGF signalling","route":"/key-papers/paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017/"},{"id":"paper-lee-clonal-history-small-cell-transformation-jco-2017","kind":"paper","name":"Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas","route":"/key-papers/paper-lee-clonal-history-small-cell-transformation-jco-2017/"},{"id":"paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016","kind":"paper","name":"Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers","route":"/key-papers/paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016/"},{"id":"paper-george-sclc-genomic-profiles-nature-2015","kind":"paper","name":"Comprehensive genomic profiles of small cell lung cancer","route":"/key-papers/paper-george-sclc-genomic-profiles-nature-2015/"},{"id":"paper-offin-rb1-tp53-transformation-risk-jto-2019","kind":"paper","name":"Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes","route":"/key-papers/paper-offin-rb1-tp53-transformation-risk-jto-2019/"},{"id":"paper-berchuck-cfdna-methylation-nepc-detection-ccr-2022","kind":"paper","name":"Detecting neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis","route":"/key-papers/paper-berchuck-cfdna-methylation-nepc-detection-ccr-2022/"},{"id":"paper-beltran-nepc-divergent-evolution-nat-med-2016","kind":"paper","name":"Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer","route":"/key-papers/paper-beltran-nepc-divergent-evolution-nat-med-2016/"},{"id":"paper-marcoux-egfr-small-cell-transformation-outcomes-jco-2019","kind":"paper","name":"EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes","route":"/key-papers/paper-marcoux-egfr-small-cell-transformation-outcomes-jco-2019/"},{"id":"paper-abida-genomic-correlates-outcome-mcrpc-pnas-2019","kind":"paper","name":"Genomic correlates of clinical outcome in advanced prostate cancer","route":"/key-papers/paper-abida-genomic-correlates-outcome-mcrpc-pnas-2019/"},{"id":"paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","kind":"paper","name":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","route":"/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/"},{"id":"paper-beltran-nepc-aurka-mycn-cancer-discov-2011","kind":"paper","name":"Molecular characterisation of neuroendocrine prostate cancer and identification of new drug targets","route":"/key-papers/paper-beltran-nepc-aurka-mycn-cancer-discov-2011/"},{"id":"paper-labrecque-mcrpc-phenotypes-jci-2019","kind":"paper","name":"Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer","route":"/key-papers/paper-labrecque-mcrpc-phenotypes-jci-2019/"},{"id":"paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","kind":"paper","name":"Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data","route":"/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/"},{"id":"paper-gay-sclc-subtypes-inflamed-cancer-cell-2021","kind":"paper","name":"Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities","route":"/key-papers/paper-gay-sclc-subtypes-inflamed-cancer-cell-2021/"},{"id":"paper-epstein-neuroendocrine-prostate-morphologic-classification-ajsp-2014","kind":"paper","name":"Proposed morphologic classification of prostate cancer with neuroendocrine differentiation","route":"/key-papers/paper-epstein-neuroendocrine-prostate-morphologic-classification-ajsp-2014/"},{"id":"paper-ku-rb1-trp53-lineage-plasticity-science-2017","kind":"paper","name":"Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance","route":"/key-papers/paper-ku-rb1-trp53-lineage-plasticity-science-2017/"},{"id":"paper-baine-sclc-subtype-immunohistochemistry-jto-2020","kind":"paper","name":"SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization","route":"/key-papers/paper-baine-sclc-subtype-immunohistochemistry-jto-2020/"},{"id":"paper-mu-sox2-lineage-plasticity-science-2017","kind":"paper","name":"SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer","route":"/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/"}],"biomarker":[{"id":"nepc-transformation","kind":"biomarker","name":"Treatment-emergent neuroendocrine transformation (recognising it)","route":"/biomarkers/nepc-transformation/"}]}}