Researchers identify promising new targets for drug-resistant breast and ovarian cancers.CU Boulder today

Researchers at CU Boulder have discovered a key role for a protein that helps breast and ovarian tumors survive and grow, and that inhibiting the protein kills cancer cells without harming healthy cells. bottom.

Findings released Tuesday journal molecular cell, identify promising new targets for treating cancers driven by specific genetic mutations, including mutations in the BRCA1 and BRCA2 genes. This research may lead to new treatments with fewer side effects and for cancers that have become resistant to existing treatments.

About 250,000 women are diagnosed with breast cancer each year, and another 20,000 are diagnosed with ovarian cancer. Her 80% of women with the most common type of ovarian cancer become treatment resistant.

“This is an important breakthrough for all cancer-resistant women who currently have nothing more to offer,” said Senior Orser, assistant professor of molecular, cellular, and developmental biology at CU Boulder. says Nausica Arnoult.

A new approach to fighting cancer

This research focuses on what is known as the DNA damage response. It is a mechanism in all cells that detects damage to the double helix that carries genetic instructions and takes steps to repair the frayed ends.

“Our DNA is constantly damaged by the sun, the chemicals we breathe, and internal processes. We and all living things have evolved mechanisms to repair that damage quickly,” Arnoult said. said.

If the repair mechanism is defective, as in the case when a person inherits a mutated copy of the BRCA1 or BRCA2 genes, some cells make mistakes and the mutation is replicated, which can lead to uncontrolled cell growth or cancer. There is a nature. Mutations can also occur sporadically due to environmental exposure or other factors.

Ironically, the same defective repair mechanisms that lead to cancer formation make cancer cells themselves susceptible to destruction.

Approximately half of ovarian cancers and a quarter of breast cancers lack a key first-line DNA repair mechanism called homologous recombination (HR), known as MMEJ (microhomology-mediated end joining). must rely on the low path of

Hoping to develop a way to disable that backup pathway, Arnoult and her team set out to better understand it. They watched damaged cancer cells in the lab, worked to repair themselves, and utilized the gene-editing tool CRISPR to identify which proteins were involved.
They found that a protein called APE2 plays an important role in repairing damaged DNA in cancer cells. When they genetically suppressed it, its DNA damage response was weakened and the cancer cells died.

On the other hand, healthy cells that could rely on the first-line DNA damage response and did not require APE2 were intact.

“Suppression of APE2 selectively kills cancer cells without affecting normal tissues, indicating that it could be a powerful target to combat breast and ovarian cancer,” Arnoult said.

Her team isn’t the first to track the DNA damage response, a vulnerability known as the ‘Achilles heel’ of cancer.

Since 2015, thousands of ovarian and breast cancer patients have been treated with so-called “PARP inhibitors,” such as the blockbuster drug olaparib, which works by disabling another backup DNA self-repair pathway. .

Unfortunately, many cancers are becoming resistant to such drugs, prompting scientists to look for other pathways and targets.

In future work, she hopes to identify small molecules that can inhibit APE2. Such inhibitors can be co-administered with other drugs to improve outcome or as a second choice when resistance develops.

Arnoult said many different types of cancer have mutations that make them more susceptible to inhibition by other DNA repair factors. A better understanding of these different pathways will allow scientists to develop new targeted therapies against a wide range of resistant cancers.

“I can’t put all my eggs in one basket anymore,” she said. “For many women, once the cancer becomes resistant, there is no second-line treatment. We need to change that.”