Researchers at Brigham and Women's Hospital have identified two new genes that can impact BRCA2-deficient cancer through "synthetic lethality," which occurs when a combination of deficiencies in two or more genes leads to cell death that would not occur with one deficiency alone.
Inactivation of BRCA1 or BRCA2, both important tumor suppressor genes named for their roles in breast cancer, increases a woman's risk of breast cancer by up to 80% and increases her risk of ovarian cancer by around 50%. In addition, BRCA mutations increase the chances of developing fallopian tube and peritoneal cancers in women, breast and prostate cancers in men, and pancreatic and colon cancers in all individuals. Cancers driven by one of the BRCA mutations are susceptible to poly(ADP-ribose) polymerase (PARP) inhibitors, but tumors can develop resistance to these drugs.
"I've been studying DNA damage response for many years and have been developing tools to look for vulnerabilities in cancer cells," commented the study's principal investigator, Stephen Elledge, PhD, the Gregor Mendel Professor of Genetics and of Medicine at Harvard Medical School and Brigham and Women's Hospital. "While 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."
For the study, published in Molecular Cell, the researchers screened two pairs of BRCA2 isogenic cell lines—cell lines engineered to accurately model the BRCA2 mutation—using DNA-repair-focused small hairpin RNA (shRNA) and CRISPR (clustered regularly interspaced short palindromic repeats). They identified two targets for BRCA-driven cancer: apurinic/apyrimidinic endodeoxyribonuclease 2 (APEX2) and flap endonuclease 1 (FEN1), both of which turned out to be synthetic lethal genes in combination with BRCA1 and BRCA2 deficiencies.
Cells with BRCA2 deficiencies require an enzyme involved in a crucial DNA repair pathway that is encoded by APEX2. Even more important to their survival is FEN1, which plays several essential roles in DNA repair during replication, including the removal of "flaps" of single-stranded DNA. The researchers found that chemically inhibiting the Fen1 protein selectively targeted BRCA-deficient cells without harming other cells.
"It will be interesting to see whether drugs targeting these genes could complement PARP inhibitors and address the issue of drug resistance," Dr. Elledge remarked, noting that medications targeting FEN1 and APEX2 are already being developed. "This work is a good example of how studies rooted in genetics and basic biology can result in therapeutic implications that could be quite profound."
For More Information
Mengwasser KE, Adeyemi RO, Leng Y, et al (2019). Genetic screens reveal FEN1 and APEX2 as BRCA2 synthetic lethal targets. Mol Cell. [Epub ahead of print] DOI:10.1016/j.molcel.2018.12.008
Image credit: Thomas Reid. Courtesy of NCI Center for Cancer Research