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PARP Inhibitors May Be Useful in HER2-Positive Breast Cancer

Discovery could broaden drugs’ clinical application (Sept. 17)

Poly (ADP-ribose) polymerase (PARP) inhibitors, shown to have clinical activity when used alone in women with familial breast and ovarian cancers linked to BRCA gene mutations, may be a novel treatment strategy in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, according to a September 17 announcement from the American Association for Cancer Research (AACR).

Currently, women with HER2-positive breast cancers are treated with therapies that target HER2. However, many women with this form of cancer either fail to ever respond to these targeted therapies or initially respond to them but then become resistant to their effects.

“Until now, PARP inhibitors have been shown to exhibit single-agent activity only in tumors that are deficient in DNA repair, such as familial breast and ovarian cancers that are linked to BRCA mutations,” said Eddy S. Yang, MD, PhD.

According to Yang, only about 5% to 10% of all breast and ovarian cancers are BRCA-associated familial cancers, so researchers are currently trying to expand the patient population that might benefit from PARP inhibitors, which are generally well tolerated and have relatively few side effects.

In prior studies, Yang’s laboratory found that inhibiting the epidermal growth factor receptor (EGFR) pathway, which is overactive in many tumor types, resulted in a DNA repair defect similar to that seen in familial cancers. The researchers subsequently showed that this “forced” DNA repair defect increased tumor sensitivity to PARP inhibitors. Because HER2 and EGFR are in the same family of proteins, Yang and his colleagues theorized that HER2-targeted therapies might force a similar DNA repair defect in HER2-positive tumors, increasing their sensitivity to PARP inhibitors.

They found that HER2-positive breast cancer cell lines were indeed sensitive to PARP inhibitors, both in culture and when transplanted into mice.

“However, the surprise was that these HER2-positive tumors were sensitive to PARP inhibitors alone, independent of a DNA repair defect,” Yang said. “This means that there may be other mechanisms, outside of DNA repair, that dictate the sensitivity of a tumor to PARP inhibitors.”

The findings were published in the AACR’s journal Cancer Research.

The researchers hope to further map out the reason why HER2-positive tumors are sensitive to PARP inhibitors. If better defined, the knowledge could ultimately broaden the clinical application of these drugs.

For more information, visit the AACR Web site.

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