{"entity":{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","aka":[],"tldr":"Cancer cells run a few genes (MYC, their lineage factors, their fusion oncogenes) at extreme volume from giant control regions called super-enhancers. The amplifiers, BRD4, CDK7, CDK9 and Mediator, are the same in every cell, but cancers are unusually dependent on them, and that dependence is druggable.","summary":"Lineage transcription factors (ER, AR, MITF, SOX2, ASCL1) and oncogenic fusions (EWSR1-FLI1, TMPRSS2-ERG, PAX3-FOXO1, NUT-BRD4) nucleate super-enhancers: clusters of enhancers densely loaded with Mediator, BRD4 (reading acetyl-lysine), p300/CBP, and cohesin loops to promoters. RNA Pol II is released from promoter-proximal pausing by P-TEFb (CDK9) and initiated by TFIIH (CDK7); CDK12/13 couple elongation to DNA-repair gene expression. MYC, itself super-enhancer-driven and amplified or ecDNA-borne, is an amplifier of all active genes. Because oncogene transcripts and proteins (MYC, MCL-1) are short-lived, transient inhibition of BET, CDK7 or CDK9 collapses them first ('transcriptional addiction'). Menin-KMT2A is a lineage-specific version (revumenib, ziftomenib in NPM1/KMT2A AML); CDK12 loss creates a tandem-duplicator phenotype in prostate cancer. Hormone receptors are the oldest transcription drugs; BET inhibitors were limited by thrombocytopenia, CDK9 inhibitors and BET/CBP degraders are in trials.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Super-enhancer","links":[{"label":"Bradner, Hnisz & Young, Transcriptional addiction in cancer (Cell 2017)","url":"https://doi.org/10.1016/j.cell.2016.12.013"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["ewing-sarcoma","aml","prostate","breast-hr-positive"],"sections":[],"technologies":["endocrine-therapy","androgen-deprivation","protac-degrader","epigenetic-drugs"],"targets":["androgen-receptor","estrogen-receptor","ewsr1-fli1","menin","kmt2a","npm1","bcl2","ezh2","irf4","ikzf1","ikzf3"],"drugs":["revumenib","ziftomenib","vepdegestrant","enzalutamide","elacestrant"],"companies":[],"institutions":[],"pathways":["myc","er-signaling","ar-signaling","epigenetic-reprogramming","swi-snf-chromatin","mrna-translation-eif4f"],"terms":["differentiation-syndrome","esr1-mutation","ar-v7"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bradner-cell"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A concert where a few songs are played at deafening volume through rented amplifiers. Cutting the mains for a moment (BET, CDK7/9 inhibitors) silences the loudest songs first because their sound decays fastest, while the quieter household appliances keep humming.","nodes":[{"id":"tf","label":"Lineage TFs (ER, AR, ASCL1)","x":12,"y":15,"targetId":"androgen-receptor"},{"id":"fus","label":"Fusion TFs (EWSR1-FLI1)","x":12,"y":48,"targetId":"ewsr1-fli1"},{"id":"se","label":"Super-enhancer","x":42,"y":30},{"id":"brd4","label":"BRD4, Mediator, p300","x":42,"y":60},{"id":"cdk7","label":"CDK7 (TFIIH) initiation","x":72,"y":15},{"id":"cdk9","label":"CDK9 (P-TEFb) elongation","x":72,"y":48},{"id":"pol","label":"RNA Pol II","x":72,"y":78},{"id":"myc","label":"MYC, MCL-1 (short-lived)","x":42,"y":90,"targetId":"bcl2"},{"id":"menin","label":"Menin-KMT2A (AML)","x":12,"y":82,"targetId":"menin"}],"edges":[{"from":"tf","to":"se","type":"activates"},{"from":"fus","to":"se","type":"activates"},{"from":"se","to":"brd4","type":"activates"},{"from":"brd4","to":"cdk7","type":"activates"},{"from":"brd4","to":"cdk9","type":"activates"},{"from":"cdk7","to":"pol","type":"activates"},{"from":"cdk9","to":"pol","type":"activates"},{"from":"pol","to":"myc","type":"activates"},{"from":"menin","to":"pol","type":"activates"}],"interventions":["Nuclear receptor drugs (endocrine therapy, ARPIs, SERDs, PROTAC vepdegestrant) are transcription drugs","Menin inhibitors revumenib and ziftomenib in KMT2A-rearranged and NPM1-mutant AML","BET inhibitors and BET/CBP degraders; CDK7 (samuraciclib) and CDK9 inhibitors in trials","Fusion-TF cancers (Ewing, NUT carcinoma) are the proving ground for transcriptional drugs"]},"route":"/pathways/transcription-addiction/","neighbours":{"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"chordoma","kind":"cancer","name":"Chordoma","route":"/cancers/chordoma/"},{"id":"ewing-sarcoma","kind":"cancer","name":"Ewing sarcoma","route":"/cancers/ewing-sarcoma/"},{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"nut-carcinoma","kind":"cancer","name":"NUT carcinoma (midline carcinoma with NUTM1 rearrangement)","route":"/cancers/nut-carcinoma/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"technology":[{"id":"androgen-deprivation","kind":"technology","name":"Androgen deprivation & AR pathway inhibitors","route":"/technologies/androgen-deprivation/"},{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"},{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"},{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"ascl1","kind":"target","name":"ASCL1","route":"/targets/ascl1/"},{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"bcl6","kind":"target","name":"BCL6","route":"/targets/bcl6/"},{"id":"brd4","kind":"target","name":"BRD4","route":"/targets/brd4/"},{"id":"cdk9","kind":"target","name":"CDK9","route":"/targets/cdk9/"},{"id":"crebbp","kind":"target","name":"CREBBP","route":"/targets/crebbp/"},{"id":"ep300","kind":"target","name":"EP300","route":"/targets/ep300/"},{"id":"estrogen-receptor","kind":"target","name":"Estrogen receptor (ERα)","route":"/targets/estrogen-receptor/"},{"id":"ewsr1-fli1","kind":"target","name":"EWSR1-FLI1 fusion","route":"/targets/ewsr1-fli1/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"ikzf1","kind":"target","name":"IKZF1 (Ikaros)","route":"/targets/ikzf1/"},{"id":"ikzf3","kind":"target","name":"IKZF3 (Aiolos)","route":"/targets/ikzf3/"},{"id":"irf4","kind":"target","name":"IRF4","route":"/targets/irf4/"},{"id":"kmt2a","kind":"target","name":"KMT2A (MLL) rearrangement","route":"/targets/kmt2a/"},{"id":"mcl1","kind":"target","name":"MCL1","route":"/targets/mcl1/"},{"id":"menin","kind":"target","name":"Menin","route":"/targets/menin/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"npm1","kind":"target","name":"NPM1 mutation","route":"/targets/npm1/"},{"id":"sox2","kind":"target","name":"SOX2","route":"/targets/sox2/"}],"drug":[{"id":"elacestrant","kind":"drug","name":"Elacestrant","route":"/drugs/elacestrant/"},{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"},{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"id":"vepdegestrant","kind":"drug","name":"Vepdegestrant","route":"/drugs/vepdegestrant/"},{"id":"ziftomenib","kind":"drug","name":"Ziftomenib","route":"/drugs/ziftomenib/"}],"pathway":[{"id":"aml-signalling","kind":"pathway","name":"Acute myeloid leukaemia (KEGG map)","route":"/pathways/aml-signalling/"},{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"mrna-translation-eif4f","kind":"pathway","name":"mRNA translation (eIF4F / mTOR)","route":"/pathways/mrna-translation-eif4f/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"id":"er-signaling","kind":"pathway","name":"Oestrogen receptor signalling","route":"/pathways/er-signaling/"},{"id":"sclc-signalling","kind":"pathway","name":"Small cell lung cancer (KEGG map)","route":"/pathways/sclc-signalling/"},{"id":"swi-snf-chromatin","kind":"pathway","name":"SWI/SNF chromatin remodelling","route":"/pathways/swi-snf-chromatin/"}],"term":[{"id":"ar-v7","kind":"term","name":"AR-V7 splice variant","route":"/terms/ar-v7/"},{"id":"differentiation-syndrome","kind":"term","name":"Differentiation syndrome","route":"/terms/differentiation-syndrome/"},{"id":"esr1-mutation","kind":"term","name":"ESR1 mutation","route":"/terms/esr1-mutation/"}],"paper":[{"id":"paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","kind":"paper","name":"Molecular determinants of resistance to antiandrogen therapy","route":"/key-papers/paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004/"},{"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-tomlins-tmprss2-ets-fusion-science-2005","kind":"paper","name":"Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer","route":"/key-papers/paper-tomlins-tmprss2-ets-fusion-science-2005/"},{"id":"paper-bradner-cell","kind":"paper","name":"Transcriptional Addiction in Cancer","route":"/key-papers/paper-bradner-cell/"}],"biomarker":[{"id":"tmprss2-erg-fusion","kind":"biomarker","name":"TMPRSS2-ERG fusion (and the other ETS rearrangements)","route":"/biomarkers/tmprss2-erg-fusion/"}],"roadmap":[{"id":"epigenetics-roadmap","kind":"roadmap","name":"Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome","route":"/roadmaps/epigenetics-roadmap/"}]}}