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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.
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.
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.
It offers the first credible explanation for why only a minority of small-cell patients get a durable benefit from checkpoint blockade, and it introduces subtype switching, which would mean retesting at relapse rather than typing once.
It gives the field a vocabulary for the states between androgen receptor-driven adenocarcinoma and small cell carcinoma, which matters because those in-between tumours are the ones most likely to be mismanaged as ordinary castration-resistant disease.
The organising framework for every small-cell lung cancer trial designed since. It is also why the slow progress in the disease is now attributed to treating four diseases as one rather than to the biology being intractable.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
The most common single molecular event in prostate cancer, present in roughly half of tumours in most series, and the reason prostate cancer is classified by fusion status. It is also a standing reminder that finding the driver and drugging it are different problems: no ETS-directed therapy has reached the clinic.
The design specification for the second-generation antiandrogens. A drug for castration-resistant prostate cancer has to stay an antagonist when the receptor is abundant, which is what enzalutamide, apalutamide and darolutamide were engineered to do and what bicalutamide fails to do.
Shares ASCL1, SOX2, Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer, Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities and the tags mechanism, mechanics-atlas.
Shares IKZF1 (Ikaros), IKZF3 (Aiolos), Vepdegestrant, MYC and the tags mechanism, mechanics-atlas.
Shares Oestrogen receptor signalling, Small cell lung cancer (KEGG map), MYC, Estrogen receptor (ERα) and the tags mechanism, mechanics-atlas.
Shares ESR1 mutation, AR-V7 splice variant, Molecular determinants of resistance to antiandrogen therapy, Elacestrant and the tags mechanism, mechanics-atlas.
Shares EZH2, Epigenetic reprogramming, BCL-2, Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET) and the tags mechanism, mechanics-atlas.
Shares IRF4, MYC, Non-Hodgkin lymphoma (all types) and the tags mechanism, mechanics-atlas.
Shares Estrogen receptor (ERα), HR-positive / HER2-negative breast cancer, Prostate cancer and the tags mechanism, mechanics-atlas.