Study Identifies Key Mutations That Make New DNA Repair Enzyme Inhibitors More Effective

Dr. Johnson
Neil Johnson, PhD, led an alternative therapies study for breast and ovarian cancers that was recently published in Nature Communications.

PHILADELPHIA (November 28, 2023) — Research into alternative therapies for breast and ovarian cancers that contain BRCA1, PALB2, or BRCA2 mutations has focused on developing new drugs targeting an enzyme that helps repair damaged DNA. But a study published in the prestigious journal Nature Communications by researchers at Fox Chase Cancer Center shows that this approach may be most effective for PALB2 and BRCA2 mutation-containing cancers.

The findings could help clinicians understand which subtypes of breast and ovarian cancers will be most sensitive to these emerging therapies, called DNA polymerase theta inhibitors. It could also be used to identify biomarkers that guide treatment decisions and predict tumor response.

“We think we can identify which patients are most likely to respond to this new type of therapy, and that’s going to be the BRCA2 and PALB2 mutation carriers,” said senior author Neil Johnson, PhD, Co-Director of the Biological Imaging Facility and a Professor in the Nuclear Dynamics and Cancer Research Program at Fox Chase. “BRCA1 mutations, on the other hand, may not be the optimal subgroup for this therapy.”

BRCA1 and BRCA2 cancers are known to be more sensitive to chemotherapies that inflict DNA damage, but they also tend to become resistant over time, creating a need for more therapeutic options.

Previous research has shown that these cancers specifically have difficulty repairing double-stranded DNA breaks, which is why scientists have focused on targeting DNA polymerase theta, an enzyme that helps repair double-stranded DNA breaks.

For the new study, Johnson’s team looked at mouse cells with a variety of different BRCA1 mutations. “We discovered that not all of the cell lines were dependent on the DNA polymerase theta enzyme for their viability,” Johnson said. “Some were, and some were not.”

They then took a closer look at the molecular functions of the BRCA1 gene to find out why. One important role of the gene is to promote DNA end resection, a process that leaves a single strand overhang at the end of a broken double-stranded DNA. The repair enzyme DNA polymerase theta uses this overhang to fix the DNA.

But researchers found that some BRCA1 gene mutations fail to trigger the resection process, leaving the break without that crucial overhang needed for the enzyme to make repairs.

In contrast, the BRCA2 and PALB2 mutations impact the DNA repair process after DNA end resection has already occurred. That means these cancers are highly dependent on DNA polymerase theta for repair, making them more sensitive to drugs that inhibit the enzyme. Johnson said researchers were initially surprised by the finding, as it contradicted previous assumptions.

“Prior to our work, the position of the field was that BRCA1 mutant cancers are highly dependent on this DNA polymerase theta enzyme, and we found there’s a significant group that are not dependent on the enzyme at all,” he said. “However, once we started to understand these pathways in more detail, it made a lot of sense.”

Next, the team plans to test DNA polymerase theta inhibitors in cell lines from human patient-derived tumors. The goal will be to see if these cancer cells, which are genetically more complex, follow the same patterns as the mouse cell lines. Ultimately, the research could be used to develop new biomarkers that guide treatment decisions, he said.

“Regardless of what their mutation might be, if we can identify whether DNA end resection is active or not, that might be a useful way to determine which patient is going to be responsive to these new types of inhibitors,” he said.

The study, “Genetic Separation of Brca1 Functions Reveal Mutation-Dependent Polθ Vulnerabilities,” was published in Nature Communications.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence six consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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