Molecular mechanisms and genomic consequences of BRCA2 and RB1 co-loss were prospectively investigated in prostate cancer cell lines. CRISPR–Cas9 and RNA interference (RNAi) methods were used to eliminate these genes in LNCaP and LAPC4 cells. Loss of BRCA2 led to a castration-resistant phenotype; co-loss of both genes induced epithelial-to-mesenchymal transition (EMT). However, PARP inhibitors attenuated cell growth in human metastatic castration-resistant prostate cancer (CRPC) organoids and CRPC cells that had single-copy loss of both genes. Thus, identification of patients with co-loss of RB1 and BRCA2 could enable early use of PARP inhibition and improve outcomes.
Chakraborty, G. et al. Significance of BRCA2 and RB1 co-loss in aggressive prostate cancer progression. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-19-1570 (2020)
Taylor, R. A. et al. The influence of BRCA2 mutation on localized prostate cancer. Nat. Rev. Urol. 16, 281–290 (2019)
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Fenner, A. BRCA2 and RB1 loss responds to PARP inhibitors. Nat Rev Urol 17, 132 (2020). https://doi.org/10.1038/s41585-020-0293-0