Another potential therapeutic approach arises from the combinatorial assembly of these complexes, specifically, at the mutually exclusive ATPase position, containing either Brg or Brm (16, 17, 19, 48). For example, loss or mutation of the Brg ATPase appears to make tumors containing these mutations highly susceptible to loss of the alternative ATPase, Brm (82). In fact, in the largest shRNA-based screen (Achilles, Broad Institute), this was the most highly ranked synthetic lethal relationship in human cancer. Similarly, in an shRNA-based screen for genes that were synthetically lethal with a mutation in BAF250a, the loss of BAF250b was detected (120). These studies indicate that when one subunit is mutated, the tumor becomes dependent on the other subunit that can occupy this position in the complex. Developmentally, BAF250a is not redundant with BAF250b and Brg is not redundant with Brm. For example, BAF250b is the most commonly mutated gene discovered in a recent exome sequencing study of human developmental diseases (58), and Brm is mutated in and causes a number of human neurodevelopmental diseases (43). Thus, therapeutic targeting of Brm or BAF250b
