Significance of BRCA2 and RB1 Co-Loss in Aggressive Prostate Cancer Progression

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TAKE-HOME MESSAGE

•This translational study conducted in human prostate cancer cell lines (LNCaP and LAPC4) was designed to assess the consequences of the loss of BRCA2 and RB1 on tumor growth and progression. The investigators demonstrated that the co-loss of BRCA2 and RB1 induces an epithelial-to-mesenchymal transition that is associated with invasion and a more aggressive disease phenotype.

•These preliminary results suggest that treatment with PARP inhibitors—therapies shown to have clinical activity in prostate cancer with alterations of genes associated with the DNA damage response—may be particularly interesting when the co-loss of BRCA2 and RB1 is identified in early prostate cancer.

– Pedro C. Barata, MD

PURPOSE

Previous sequencing studies revealed that alterations of genes associated with DNA damage response (DDR) are enriched in men with metastatic castration-resistant prostate cancer (mCRPC). BRCA2, a DDR and cancer susceptibility gene, is frequently deleted (homozygous and heterozygous) in men with aggressive prostate cancer. Here we show that prostate cancer patients who have lost a copy of BRCA2 frequently lose a copy of tumor-suppressor gene RB1; importantly, for the first time we demonstrate that co-loss of both genes in early prostate cancer is sufficient to induce a distinct biology that is likely associated with worse prognosis.

EXPERIMENTAL DESIGN

We prospectively investigated underlying molecular mechanisms and genomic consequences of co-loss of BRCA2 and RB1 in prostate cancer. We used CRISPR-Cas9 and RNAi-based methods to eliminate these two genes in prostate cancer cell lines and subjected them to in-vitro studies and transcriptomic analyses. We developed a 3-color FISH assay to detect genomic deletions of BRCA2 and RB1 in prostate cancer cells and patient-derived mCRPC organoids.

RESULTS

In human prostate cancer cell lines (LNCaP and LAPC4), loss of BRCA2 leads to the castration-resistant phenotype. Co-loss of BRCA2-RB1 in human prostate cancer cells induces an epithelial-to-mesenchymal transition which is associated with invasiveness and a more aggressive disease phenotype. Importantly, PARP inhibitors attenuate cell growth in human mCRPC-derived organoids and human CRPC cells harboring single-copy loss of both genes.

CONCLUSIONS

Our findings suggest that early identification of this aggressive form of prostate cancer offers potential for improved outcomes with early introduction of PARP inhibitor-based therapy.

Clinical Cancer Research

Significance of BRCA2 and RB1 Co-Loss in Aggressive Prostate Cancer Progression

Clin. Cancer Res 2019 Dec 03;[EPub Ahead of Print], G Chakraborty, J Armenia, YZ Mazzu, S Nandakumar, KH Stopsack, MO Atiq, K Komura, L Jehane, R Hirani, K Chadalavada, Y Yoshikawa, NA Khan, Y Chen, W Abida, LA Mucci, GM Lee, GJ Nanjangud, PW Kantoff

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine