Combining a PI3K inhibitor with a PARP inhibitor may be an effective therapy for triple-negative breast cancer, researchers have determined.

Because triple-negative breast cancers do not express three common targets of breast cancer treatments, including the estrogen receptor, progesterone receptor, and HER2/neu, treatment options are limited to chemotherapeutic regimens that have considerable toxicity and are not curative, explain the investigators in Cancer Discovery (2012;2[11]:1048-1063). In early-phase clinical studies, women with triple-negative breast cancer and BRCA1 gene mutations exhibited some clinical benefit from treatments with poly (ADP-ribose) polymerase (PARP) inhibitors, but the activity of these drugs is short-lived.

In the current study, the investigators sought to increase the sensitivity of triple-negative breast cancers to PARP inhibitors by blocking phosphoinositide 3-kinase (PI3-kinase). PI3-kinase is a key component of a signaling pathway frequently activated inappropriately in triple-negative breast cancer. Working with mice, the researchers found that blocking PI3-kinase function in a BRCA-proficient triple-negative breast cancer cell line would result in DNA damage, and PARP would be activated to repair the damage. Cells then became sensitive to PARP inhibition.


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The team’s report also describes a second project, in which the investigators observed that mice with a BRCA1–deficient breast cancer had molecular indicators of strong activation of the P13-kinase pathway. This suggested that the tumors might be vulnerable to P13-kinase inhibitors. When the mice were given these drugs, tumor doubling was delayed from 5 days to 26 days. Adding a PARP inhibitor to the mix delayed tumor doubling to more than 70 days.