Finding Deadly Partners

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Researchers identify a new set of targets for treating cancers with BRCA1 mutations.
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(L-R) Dr. Razq Hakem, Senior Scientist at the Princess Margaret Cancer Centre and senior author of the study; first authors of the study: Dr. Parasvi S. Patel (former PhD student), Arash Algouneh (former MSc student) and Dr. Rehna Krishnan (postdoctoral researcher).

A research team led by Senior Scientist Dr. Razq Hakem at the Princess Margaret Cancer Centre has identified new potential therapeutic targets for breast and ovarian cancers with mutations in the BRCA1 gene.

BRCA1 plays a key role in repairing damaged DNA, but when mutated, is unable to make the necessary repairs. This can lead to a higher risk of developing breast or ovarian cancer. Given that BRCA1-mutant cancers can be difficult to treat, given that they tend to be more aggressive and resistant to standard therapies. Thus, it is important to find new ways to target them.  

“One way to target BRCA1-mutated cancers is to look at a concept known as synthetic lethality,” says Dr. Hakem. “Synthetic lethality occurs when the loss of function of two genes leads to cancer cell death. Importantly, loss of just one of the two genes is not enough—the cancer cells can still survive if one of the genes is still functioning.”

This concept has already led to new therapies to treat cancer, including drugs that target the poly (ADP-ribose) polymerase (PARP) gene—a synthetic lethal partner of BRCA1 that is also involved in repairing DNA damage. While PARP inhibitors have been approved for cancers with BRCA1 mutations in certain settings, some cancers become resistant to the therapy.

To address this, the team sought to find other synthetic lethal partners of BRCA1 that were not involved in DNA repair. By using a technique called a CRISPR-Cas9 screen, the researchers found that the depletion of a gene called methylphosphate capping enzyme (MEPCE) was lethal in BRCA1-mutant cancer cells.

Further, they found that the loss of MEPCE results in a highly unstable genome in BRCA1-mutant breast and ovarian cancer cells. Loss of MEPCE also impaired the ability of the cells to copy and replicate DNA, and revealed other molecules involved in these processes as potential therapeutic targets.                                                                                                

"Our findings provide new insights into the molecular mechanisms underlying the synthetic lethality of BRCA1 mutations and identify new class of therapeutic targets for treating BRCA1-mutant tumors that have become resistant to standard therapies," says Dr. Hakem.

This work was supported by the Terry Fox Foundation, the University of Toronto, the Government of Ontario, the Canadian Institutes of Health Research, the Canadian Cancer Society, the Cancer Research Society, Cancer Research UK, the University of Birmingham, the Samuel Waxman Cancer Research Foundation, the Carlos III Institute of Health, the European Development Fund, the Bellvitge Biomedical Research Institute, and The Princess Margaret Cancer Foundation. Dr. Razq Hakem is a Professor of Medical Biophysics at the University of Toronto and holds a Lee K. and Margaret Lau Chair in Breast Cancer Research.

Dr. Pujana is the recipient of an unrestricted research grant from Roche Pharma for the support of the ProCURE study.

Patel PS#, Algouneh A#, Krishnan R#, Reynolds JJ, Nixon KCJ, Hao J, Lee J, Feng Y, Fozil C, Stanic M, Yerlici T, Su P, Soares F, Liedtke E, Prive G, Baider GD, Pujana MA, Mekhail K, He HH, Hakem A, Stewart GS, Hakem R. Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers. Nucleic Acids Res. 2023 Mar 17. DOI: 10.1093/nar/gkad172. #contributed equally

Each cell has several DNA repair proteins that help correct different types of errors or breaks in the genome. BRCA1 specifically repairs double stranded breaks in DNA.