BRCA1 and BRCA2 (鈥淏Reast CAncer genes鈥�) are critical tumor suppressor genes鈥攚omen carrying a mutation in one of these genes have up to an 80 percent risk of developing breast cancer and a 50 percent risk of developing ovarian cancer. Cancer drugs known as Parp inhibitors have recently been approved for treating patients with BRCA-driven metastatic breast cancer or recurrent ovarian cancer, but many patients鈥� cancers become resistant to the drugs. New drug targets for treating BRCA-driven cancer are urgently needed. Investigators from Brigham and Women鈥檚 Hospital have conducted a study to systematically identify new genetic targets on which BRCA2 cancer cells are more dependent than healthy cells and have tested these targets in the lab. Such 鈥渟ynthetic lethals鈥� point to potential avenues for drug development. The team鈥檚 findings are published in Molecular Cell.

鈥淚鈥檝e been studying DNA damage response for many years and have been developing tools to look for vulnerabilities in cancer cells,鈥� said corresponding author Stephen Elledge, PhD, the Gregor Mendel Professor of Genetics and of Medicine at Harvard Medical School and 天美传媒l. 鈥淲hile Parp inhibitors are important, many people are developing resistance to them. We thought we might be able to find other pathways through which we could effectively kill cancer cells without harming normal cells.鈥�

To search for new targets, lead author Kristen Mengwasser, an MD-PhD student at Harvard Medical School, Elledge and colleagues, used CRISPR and short-hairpin RNAs (shRNAs) to test 380 genes with a known or suspected role in DNA-damage response. The team carried out its tests in a pair of colon cancer cell lines鈥攐ne with a BRCA2 mutation and one without鈥攁nd in a pair of ovarian cancer cell lines. These screens and follow-up experiments helped the researchers narrow in on the two most promising targets: APEX2 and FEN1. Neither gene has been reported previously as a potential target for BRCA-driven cancer.

The team鈥檚 strongest finding was the flap endonuclease FEN1. When working appropriately, this enzyme plays several essential roles in DNA repair events, including removing 鈥渇laps鈥� (overhangs of single-stranded DNA) during DNA replication. Normal cells can survive without it, but in cancer cells in which both copies of BRCA2 have been compromised, the loss of FEN1 results in cell death. The team found similar results for APEX2, which encodes an enzyme involved in another important DNA repair pathway. The team tested an existing FEN1 inhibitor on cells in the lab and found that it preferentially killed cancer cells with the BRCA mutation.

Elledge notes that drugs targeting FEN1 and APEX2 are currently in production at small start-up companies.

鈥淚t will be interesting to see whether drugs targeting these genes could complement Parp inhibitors and address the issue of drug resistance,鈥� said Elledge. 鈥淭his work is a good example of how studies rooted in genetics and basic biology can result in therapeutic implications that could be quite profound.鈥�

This work was supported by a grant from the National Cancer Institute and Department of Defense Award W81XWH-12-1-0362.

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