Nav: Home

New drug targets for BRCA-driven cancer uncovered

January 24, 2019

BRCA1 and BRCA2 ("BReast CAncer genes") are critical tumor suppressor genes--women 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' cancers become resistant to the drugs. New drug targets for treating BRCA-driven cancer are urgently needed. Investigators from Brigham and Women's 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 "synthetic lethals" point to potential avenues for drug development. The team's findings are published in Molecular Cell.

"I've been studying DNA damage response for many years and have been developing tools to look for vulnerabilities in cancer cells," said corresponding author 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."

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--one with a BRCA2 mutation and one without--and 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's strongest finding was the flap endonuclease FEN1. When working appropriately, this enzyme plays several essential roles in DNA repair events, including removing "flaps" (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.

"It will be interesting to see whether drugs targeting these genes could complement Parp inhibitors and address the issue of drug resistance," said Elledge. "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."
-end-
This work was supported by a grant from the National Cancer Institute and Department of Defense Award W81XWH-12-1-0362.

Brigham and Women's Hospital

Related Cancer Cells Articles:

Scientists have identified the presence of cancer-suppressing cells in pancreatic cancer
Researchers have identified cells containing a protein called Meflin that has a role in restraining the progression of pancreatic cancer.
Changes in the metabolism of normal cells promotes the metastasis of ovarian cancer cells
A systematic examination of the tumor and the tissue surrounding it -- particularly normal cells in that tissue, called fibroblasts -- has revealed a new treatment target that could potentially prevent the rapid dissemination and poor prognosis associated with high-grade serous carcinoma (HGSC), a tumor type that primarily originates in the fallopian tubes or ovaries and spreads throughout the abdominal cavity.
The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.
White blood cells related to allergies may also be harnessed to destroy cancer cells
A new Tel Aviv University study finds that white blood cells which are responsible for chronic asthma and modern allergies may be used to eliminate malignant colon cancer cells.
Conversion of breast cancer cells into fat cells impedes the formation of metastases
An innovative combination therapy can force malignant breast cancer cells to turn into fat cells.
Breast cancer cells in mice tricked into turning into fat cells
As cancer cells respond to cues in their microenvironment, they can enter a highly plastic state in which they are susceptible to transdifferentiation into a different type of cell.
Brain cancer: Typical mutation in cancer cells stifles immune response
The exchange of a single amino acid building block in a metabolic enzyme can lead to cancer.
Researchers find prostate cancer drug byproduct can fuel cancer cells
A genetic anomaly in certain men with prostate cancer may impact their response to common drugs used to treat the disease, according to new research at Cleveland Clinic.
Dying cancer cells make remaining glioblastoma cells more aggressive and therapy-resistant
A surprising form of cell-to-cell communication in glioblastoma promotes global changes in recipient cells, including aggressiveness, motility, and resistance to radiation or chemotherapy.
An index measures similarity between cancer cells and pluripotent stem cells
The new methodology measures tumor aggressiveness and the risk of relapse, helping doctors plan treatment, according to Brazilian scientists authors of a paper published in a special issue of the journal Cell.
More Cancer Cells News and Cancer Cells Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#538 Nobels and Astrophysics
This week we start with this year's physics Nobel Prize awarded to Jim Peebles, Michel Mayor, and Didier Queloz and finish with a discussion of the Nobel Prizes as a way to award and highlight important science. Are they still relevant? When science breakthroughs are built on the backs of hundreds -- and sometimes thousands -- of people's hard work, how do you pick just three to highlight? Join host Rachelle Saunders and astrophysicist, author, and science communicator Ethan Siegel for their chat about astrophysics and Nobel Prizes.