Defective microhomology-mediated end joining in SMARCB1-deficient tumors

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Rhabdoid tumors (RTs) are aggressive cancers characterized by biallelic mutations in the *SMARCB1* gene.
• *SMARCB1* is a crucial component of the BAF (SWI/SNF) chromatin remodeling complex.
• The underlying molecular mechanisms driving RT progression and potential therapeutic vulnerabilities are actively investigated.

Purpose of the Study:

• To investigate the role of *SMARCB1* in DNA repair pathways in rhabdoid tumors.
• To identify potential therapeutic targets for *SMARCB1*-deficient cancers.
• To explore the compensatory DNA repair mechanisms activated in RTs.

Main Methods:

• Analysis of DNA repair pathway defects in *SMARCB1*-deficient tumor models.
• Investigating the interaction of SMARCB1 with DNA Polymerase theta (PolΘ) and its mRNA (*POLQ*).
• Evaluating the efficacy of RBM39 degraders targeting the Fanconi Anemia (FA)/BRCA pathway in vitro and in vivo.

Main Results:

• *SMARCB1*-deficient tumors exhibit a defect in the microhomology-mediated end joining (MMEJ) DNA repair pathway.
• SMARCB1 is essential for maintaining PolΘ protein levels by facilitating *POLQ* mRNA nuclear export.
• Loss of MMEJ leads to compensatory activation and hyper-dependence on the FA/BRCA pathway in RT cells.
• RBM39 degraders demonstrate significant antitumor activity by disrupting the FA/BRCA pathway.

Conclusions:

• *SMARCB1* loss impairs MMEJ, creating a vulnerability in the FA/BRCA pathway in rhabdoid tumors.
• Targeting the FA/BRCA pathway, for instance, with RBM39 degraders, is a viable therapeutic strategy for RTs.
• This suggests that BAF-deficient cancers may broadly benefit from targeted inhibition of the FA/BRCA pathway.