SMARCB1 Deficiency as a Driver of the Hallmarks of Cancer in Rhabdoid Tumours: Novel Insights into Dysregulated Energy Metabolism, Emerging Targets, and Ongoing Clinical Trials

Rhabdoid tumours (RTs) are aggressive neoplasms most often characterised by biallelic loss of the SMARCB1 gene, which encodes a core subunit of the SWI/SNF chromatin remodelling complex. Despite their relative genetic stability, RTs exhibit a highly malignant phenotype and poor prognosis. This review aims to explore the mechanisms underlying SMARCB1 aberrations, their role in driving hallmarks of cancer, and emerging therapeutic strategies for RTs. The loss of SMARCB1 drives multiple cancer hallmarks by disrupting key regulatory pathways. It promotes unchecked cell proliferation through alterations in p16INK4a and Myc signalling. SMARCB1-deficient tumours possess immune evading capabilities via PD-L1 overexpression and immune checkpoint activation. SMARCB1 deficiency also alters cellular energetics by various mechanisms. The nucleotide biosynthesis pathway has been demonstrated to be upregulated in RT organoids, as shown by increased levels of pathway metabolites. Enzymes of the mevalonate pathway such as HMG-CoA reductase and mevalonate kinase are also dysregulated. Targeting glutathione metabolism with eprenetapopt may result in oxidative stress and induce apoptosis in RTs. Widespread epigenetic aberrations, including increased EZH2 activity, are being targeted with inhibitors such as tazemetostat. Future horizons in RT treatment include immunotherapies, epigenetic modifiers, and gene therapies. The synergy and optimal timing of targeted therapy with conventional treatment needs to be better characterised in order to proceed to later stage clinical trials and clinical practice.