SRS357 - Disrupting cellular hypoxia response in neuroblastoma tumourigenesis by PROTAC-mediated SWI/SNF ATPase degradation

Abstract Background Neuroblastoma is a childhood cancer with devastatingly poor prognosis, arising from dysregulated developmental programs in fetal adrenal progenitors. Aberrant cellular hypoxia response, mediated by hypoxia inducible factors (HIFs), and SWI/SNF chromatin remodelling are implicated in pathogenesis. We investigated both the role of hypoxia in neuroblastoma development and the therapeutic potential of SMARCA2/4 PROTACs, which degrade SWI/SNF ATPases via the VHL-proteasome pathway. Methods and Results Bulk RNA-sequencing of SK-N-AS and SH-SY5Y cells under normoxia and hypoxia, together with meta-analysis of 60 datasets, defined a core neuroblastoma hypoxia signature predictive of poor patient survival. Signature scoring in a fetal adrenal single-cell dataset revealed chromaffin cells as the most hypoxia-responsive and SWI/SNF ATPase-dependent, directly implicating the cellular hypoxia response in adrenal gland embryology. 2D in-vitro and 3D-spheroid analyses were performed to study the effect of SMARCA2/4 PROTACs on cell viability, migration, cell cycle, and expression of SWI/SNF subunits, HIF, and downstream targets. In vivo efficacy was evaluated in a chick embryo xenograft model. PROTAC treatment reduced viability, migration, spheroid growth, and tumour formation, while mechanistically suppressing HIF activity through reduced HIF-1α and RNA Pol II binding at hypoxia-inducible promoters. RNA-seq and qPCR validation identified significant downregulation of previously uncharacterised hypoxia genes specific to neuroblastoma and chromaffin identity, as well as upregulation of differentiation-associated genes. Conclusions Our findings establish the cellular hypoxia response as central to adrenal gland embryology and neuroblastoma pathogenesis. PROTAC-mediated degradation of SWI/SNF ATPases suppresses these programs and reduces tumourigenesis, highlighting a promising therapeutic avenue.