Defective Microhomology-Mediated End-joining in SMARCB1-Deficient Tumors

Area of Science:

• Oncology
• Cancer Biology
• Molecular Biology

Background:

• Rhabdoid tumors (RTs) are aggressive cancers linked to mutations in SMARCB1, a key component of the BAF (SWI/SNF) complex.
• SMARCB1 loss impairs the microhomology-mediated end-joining (MMEJ) DNA repair pathway.

Purpose of the Study:

• To investigate the functional consequences of SMARCB1 loss on DNA repair pathways in RTs.
• To identify therapeutic vulnerabilities in SMARCB1-deficient cancers.

Main Methods:

• Assessed DNA repair pathway activity in SMARCB1-deficient RT cells.
• Investigated the role of SMARCB1 in maintaining Polymerase Q (POLQ) protein levels and its mRNA export.
• Evaluated the efficacy of targeting the Fanconi Anemia (FA)/BRCA pathway and using RBM39 degraders.

Main Results:

• SMARCB1-deficient tumors exhibit MMEJ pathway defects due to reduced POLQ protein levels, caused by impaired POLQ mRNA nuclear export.
• RT cells compensate for MMEJ deficiency by hyper-activating the FA/BRCA pathway.
• Inhibition of the FA/BRCA pathway, including with RBM39 degraders, selectively eliminates RT cells.

Conclusions:

• SMARCB1 is crucial for MMEJ pathway integrity by regulating POLQ levels.
• The FA/BRCA pathway is a critical vulnerability in SMARCB1-deficient RTs.
• Targeting the FA/BRCA pathway represents a promising therapeutic strategy for BAF-deficient cancers.