Inhibition of both SWI/SNF ATPases by BRM014 impairs homologous recombination, sensitizes cells to DNA damage and PARP inhibitors, and activates the cGAS/STING response.

SWI/SNF chromatin remodelers hydrolyze ATP to modulate chromatin accessibility and are mutated in up to 20 % of human cancers. The development of ATPase inhibitors and proteolysis targeting chimeras (PROTACs) have shown that SWI/SNF complexes can be therapeutic targets against cancers that require MYC expression for their survival (e.g., leukemias, prostate cancer, uveal melanoma). In this study we show that for cancers that do not depend on MYC expression, inhibition of both SWI/SNF ATPases by BRM014 impairs homologous recombination (HR) and sensitizes U2OS osteosarcoma cells and MDA-MB-231 triple negative breast cancer cells to chemotherapeutic agents that induce DNA double strand breaks (DSBs) and importantly, to PARP inhibitors (PARPi). BRM014 impaired DSB repair and the clearance of γH2AX foci. Moreover, BRM014 stimulated the use of non-homologous end joining (NHEJ) for DSB repair. Finally, BRM014 alone or in combination with olaparib also increased the frequency of micronuclei formation and activated the cGAS/STING response mediated by the activation of NFκB. Similar results were observed by inducing the degradation of both SWI/SNF ATPases by a PROTAC (AU-15330), which impaired the repair of DSBs, sensitized cells to DNA damage and PARPi. This study shows that inhibition or degradation of both SWI/SNF ATPases enhances the effects of chemotherapy, and activates the cGAS/STING response, which is associated with better therapeutic outcomes. This study shows that SWI/SNF chromatin remodelers are an important target to enhance the effects of chemotherapy and can affect the choice of DSB repair pathway.