SWI/SNF chromatin remodelling
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.
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SMARCA4-loss → SMARCA2 (degraders in trials), ARID1A-loss → EZH2/ATR/PARP, SMARCB1-loss → EZH2 (tazemetostat, withdrawn 2026 for safety).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.
In one picture
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.
Diagram
top- 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- EZH2 inhibition in SMARCB1-deficient tumours (tazemetostat withdrawn 2026)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
Notes
top- Leading programmes: Kadoch (Dana-Farber/Broad) on SWI/SNF structure and Foghorn Therapeutics; Crabtree (Stanford); Roberts (St. Jude) on SMARCB1.
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