{"entity":{"id":"swi-snf-chromatin","kind":"pathway","name":"SWI/SNF chromatin remodelling","aka":[],"tldr":"A machine that opens and closes DNA so genes can be read. One in five cancers has a broken part (ARID1A, SMARCA4, PBRM1), and losing one part often creates a dependence on its twin, which is the basis for new synthetic-lethal drugs.","summary":"SWI/SNF (BAF, PBAF, ncBAF) complexes remodel nucleosomes; subunits are mutated in ~20% of cancers: ARID1A (ovarian clear cell, endometrial, bladder), SMARCA4 (lung, SCCOHT), PBRM1 (clear-cell RCC), SMARCB1 (rhabdoid tumours, epithelioid sarcoma). Dependencies: SMARCA4-loss → SMARCA2 (degraders in trials), ARID1A-loss → EZH2/ATR/PARP, SMARCB1-loss → EZH2 (tazemetostat, withdrawn 2026 for safety). PBRM1 loss associates with IO response in RCC (debated). FHD-286 (BRM/BRG1 inhibitor) is in AML trials.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/SWI/SNF","links":[{"label":"Centore, Sandoval, Soares, Kadoch & Chan, Mammalian SWI/SNF chromatin remodeling complexes (Trends in Genetics 2020)","url":"https://doi.org/10.1016/j.tig.2020.07.011"}],"tags":["mechanism"],"related":[],"cancers":["rcc","ovarian","nsclc","sarcoma"],"sections":[],"technologies":["synthetic-lethality-approaches","protac-degrader"],"targets":["ezh2","atr"],"drugs":[],"companies":[],"institutions":["dana-farber","broad-institute","stanford"],"pathways":["epigenetic-reprogramming","cancer-stem-cells-plasticity","replication-stress"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-centore-trends-genet"],"journals":[],"dependsOn":[],"notes":["Leading programmes: Kadoch (Dana-Farber/Broad) on SWI/SNF structure and Foghorn Therapeutics; Crabtree (Stanford); Roberts (St. Jude) on SMARCB1."],"analogy":"A librarian who unlocks shelves on request. When one librarian is fired the other covers both shifts; fire the second and the library stops working. That second librarian is the drug target.","nodes":[{"id":"baf","label":"BAF / PBAF / ncBAF","x":40,"y":30},{"id":"nuc","label":"Nucleosome repositioning","x":70,"y":30},{"id":"tx","label":"Enhancer access, differentiation genes","x":90,"y":55},{"id":"arid","label":"ARID1A loss","x":12,"y":20},{"id":"smarca4","label":"SMARCA4 loss → SMARCA2 dependence","x":12,"y":50},{"id":"smarcb1","label":"SMARCB1 loss → EZH2","x":12,"y":80,"targetId":"ezh2"},{"id":"prc2","label":"PRC2 (EZH2) antagonism","x":60,"y":75,"targetId":"ezh2"}],"edges":[{"from":"baf","to":"nuc","type":"activates"},{"from":"nuc","to":"tx","type":"activates"},{"from":"arid","to":"baf","type":"inhibits"},{"from":"smarca4","to":"baf","type":"inhibits"},{"from":"smarcb1","to":"baf","type":"inhibits"},{"from":"prc2","to":"tx","type":"inhibits"},{"from":"baf","to":"prc2","type":"inhibits"}],"interventions":["SMARCA2 degraders (PRT3789, PRT7732) in SMARCA4-mutant cancers (phase 1/2)","EZH2 inhibition in SMARCB1-deficient tumours (tazemetostat withdrawn 2026)","ATR/PARP inhibitors in ARID1A-mutant tumours (trials)","FHD-286 in AML"]},"route":"/pathways/swi-snf-chromatin/","neighbours":{"cancer":[{"id":"atrt","kind":"cancer","name":"Atypical teratoid/rhabdoid tumour (ATRT)","route":"/cancers/atrt/"},{"id":"chordoma","kind":"cancer","name":"Chordoma","route":"/cancers/chordoma/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"epithelioid-sarcoma","kind":"cancer","name":"Epithelioid sarcoma","route":"/cancers/epithelioid-sarcoma/"},{"id":"sinonasal","kind":"cancer","name":"Nasal cavity and paranasal sinus cancers (including esthesioneuroblastoma)","route":"/cancers/sinonasal/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"rcc","kind":"cancer","name":"Renal cell carcinoma","route":"/cancers/rcc/"},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"}],"technology":[{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"target":[{"id":"arid1a","kind":"target","name":"ARID1A","route":"/targets/arid1a/"},{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"smarca2","kind":"target","name":"SMARCA2","route":"/targets/smarca2/"},{"id":"smarca4","kind":"target","name":"SMARCA4","route":"/targets/smarca4/"},{"id":"smarcb1","kind":"target","name":"SMARCB1","route":"/targets/smarcb1/"}],"institution":[{"id":"broad-institute","kind":"institution","name":"Broad Institute of MIT and Harvard","route":"/institutions/broad-institute/"},{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"stanford","kind":"institution","name":"Stanford Health Care / Stanford Cancer Institute","route":"/institutions/stanford/"}],"pathway":[{"id":"cancer-stem-cells-plasticity","kind":"pathway","name":"Cancer stem cells & phenotypic plasticity","route":"/pathways/cancer-stem-cells-plasticity/"},{"id":"replication-stress","kind":"pathway","name":"DNA replication stress","route":"/pathways/replication-stress/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"}],"paper":[{"id":"paper-hayashi-squamous-basal-like-pancreatic-nat-cancer-2020","kind":"paper","name":"A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma","route":"/key-papers/paper-hayashi-squamous-basal-like-pancreatic-nat-cancer-2020/"},{"id":"paper-campbell-pan-lung-somatic-alterations-nat-genet-2016","kind":"paper","name":"Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas","route":"/key-papers/paper-campbell-pan-lung-somatic-alterations-nat-genet-2016/"},{"id":"paper-bailey-molecular-subtypes-pancreatic-nature-2016","kind":"paper","name":"Genomic analyses identify molecular subtypes of pancreatic cancer","route":"/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/"},{"id":"paper-centore-trends-genet","kind":"paper","name":"Mammalian SWI/SNF Chromatin Remodeling Complexes: Emerging Mechanisms and Therapeutic Strategies","route":"/key-papers/paper-centore-trends-genet/"},{"id":"paper-biankin-pancreatic-exomes-axon-guidance-nature-2012","kind":"paper","name":"Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes","route":"/key-papers/paper-biankin-pancreatic-exomes-axon-guidance-nature-2012/"},{"id":"paper-schoenfeld-smarca4-alterations-lung-ccr-2020","kind":"paper","name":"The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer","route":"/key-papers/paper-schoenfeld-smarca4-alterations-lung-ccr-2020/"}],"term":[{"id":"epigenetic-progenitor-theory","kind":"term","name":"Epigenetic progenitor theory: cancer without a first mutation","route":"/terms/epigenetic-progenitor-theory/"},{"id":"nonmutational-epigenetic-reprogramming","kind":"term","name":"Hallmark (2022): non-mutational epigenetic reprogramming","route":"/terms/nonmutational-epigenetic-reprogramming/"}],"roadmap":[{"id":"epigenetics-roadmap","kind":"roadmap","name":"Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome","route":"/roadmaps/epigenetics-roadmap/"}]}}