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;2:1048-1063). 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.
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.