Specific killing of BRCA1-deficient cancer cells by depletion of EXO1
Haico van Attikum
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
BRCA1 and BRCA2 are essential genome maintenance factors that function in the repair of DNA Double-Strand Breaks (DSBs) by homologous recombination (HR). Cancer patients that carry tumors with loss-of-function mutations in BRCA1 or BRCA2 often benefit from treatment with PARP inhibitor therapy, which specifically kills HR-deficient tumor cells. However, clinical responses are rarely long-lasting due to resistance to PARP inhibitor treatment. We therefore sought to identify novel therapeutic opportunities to treat HR-deficient tumors. Our studies revealed that genetic inactivation of the exonuclease EXO1 is severely toxic to BRCA1-deficient cells, but not to BRCA1-proficient cells. In my seminar I will present the mechanistic basis of this finding, highlighting EXO1 as a novel target with therapeutic potential for BRCA1-deficient tumors.