# Transcriptional machinery & addiction

Source: https://onco.cc/pathways/transcription-addiction/  
OnCo record `transcription-addiction` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

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

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Super-enhancer
- Bradner, Hnisz & Young, Transcriptional addiction in cancer (Cell 2017): https://doi.org/10.1016/j.cell.2016.12.013

## Connected records

- cancers: [Acute myeloid leukaemia](https://onco.cc/cancers/aml/), [Chordoma](https://onco.cc/cancers/chordoma/), [Ewing sarcoma](https://onco.cc/cancers/ewing-sarcoma/), [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [NUT carcinoma (midline carcinoma with NUTM1 rearrangement)](https://onco.cc/cancers/nut-carcinoma/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/)
- technologies: [Androgen deprivation & AR pathway inhibitors](https://onco.cc/technologies/androgen-deprivation/), [Endocrine therapy (SERMs, AIs, SERDs)](https://onco.cc/technologies/endocrine-therapy/), [Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/), [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [ASCL1](https://onco.cc/targets/ascl1/), [BCL-2](https://onco.cc/targets/bcl2/), [BCL6](https://onco.cc/targets/bcl6/), [BRD4](https://onco.cc/targets/brd4/), [CDK9](https://onco.cc/targets/cdk9/), [CREBBP](https://onco.cc/targets/crebbp/), [EP300](https://onco.cc/targets/ep300/), [Estrogen receptor (ERα)](https://onco.cc/targets/estrogen-receptor/), [EWSR1-FLI1 fusion](https://onco.cc/targets/ewsr1-fli1/), [EZH2](https://onco.cc/targets/ezh2/), [IKZF1 (Ikaros)](https://onco.cc/targets/ikzf1/), [IKZF3 (Aiolos)](https://onco.cc/targets/ikzf3/), [IRF4](https://onco.cc/targets/irf4/), [KMT2A (MLL) rearrangement](https://onco.cc/targets/kmt2a/), [MCL1](https://onco.cc/targets/mcl1/), [Menin](https://onco.cc/targets/menin/), [MYC](https://onco.cc/targets/myc-gene/), [NPM1 mutation](https://onco.cc/targets/npm1/), [SOX2](https://onco.cc/targets/sox2/)
- drugs: [Elacestrant](https://onco.cc/drugs/elacestrant/), [Enzalutamide](https://onco.cc/drugs/enzalutamide/), [Revumenib](https://onco.cc/drugs/revumenib/), [Vepdegestrant](https://onco.cc/drugs/vepdegestrant/), [Ziftomenib](https://onco.cc/drugs/ziftomenib/)
- pathways: [Acute myeloid leukaemia (KEGG map)](https://onco.cc/pathways/aml-signalling/), [Androgen receptor signalling](https://onco.cc/pathways/ar-signaling/), [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [mRNA translation (eIF4F / mTOR)](https://onco.cc/pathways/mrna-translation-eif4f/), [MYC](https://onco.cc/pathways/myc/), [Oestrogen receptor signalling](https://onco.cc/pathways/er-signaling/), [Small cell lung cancer (KEGG map)](https://onco.cc/pathways/sclc-signalling/), [SWI/SNF chromatin remodelling](https://onco.cc/pathways/swi-snf-chromatin/)
- terms: [AR-V7 splice variant](https://onco.cc/terms/ar-v7/), [Differentiation syndrome](https://onco.cc/terms/differentiation-syndrome/), [ESR1 mutation](https://onco.cc/terms/esr1-mutation/)
- key papers: [Molecular determinants of resistance to antiandrogen therapy](https://onco.cc/key-papers/paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004/), [Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-labrecque-mcrpc-phenotypes-jci-2019/), [Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data](https://onco.cc/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/), [Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities](https://onco.cc/key-papers/paper-gay-sclc-subtypes-inflamed-cancer-cell-2021/), [Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer](https://onco.cc/key-papers/paper-tomlins-tmprss2-ets-fusion-science-2005/), [Transcriptional Addiction in Cancer](https://onco.cc/key-papers/paper-bradner-cell/)
- biomarkers: [TMPRSS2-ERG fusion (and the other ETS rearrangements)](https://onco.cc/biomarkers/tmprss2-erg-fusion/)
- roadmaps: [Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome](https://onco.cc/roadmaps/epigenetics-roadmap/)

---
JSON: https://onco.cc/api/v1/entities/transcription-addiction.json