HDAC inhibitors sensitize triple-negative breast cancer cells to PARP inhibition and cisplatin

In vitro exposure to an HDAC inhibitor indirectly impaired the ability of triple-negative breast cancer cells to repair damaged DNA, and sensitized the cells to treatment with two therapies that have clinical activity in some patients with breast cancer: a PARP inhibitor and cisplatin.

“Triple-negative breast cancer is a particularly aggressive breast cancer that is not susceptible to traditional hormone therapies,” said Kapil N. Bhalla, MD, of the University of Kansas Cancer Center in Kansas City. “That is why it is important to try to find new ways of killing triple-negative breast cancer cells.”

Cells of certain human tumors rely on intact DNA repair pathways for survival. Prior research has shown that proteins such as ATR, CHK1 and BRCA1 are essential parts of a cell's response to DNA damage and its subsequent repair of the damage. These three proteins are controlled or chaperoned by heat shock protein 90 (hsp90). Previously, Bhalla and colleagues had found that treatment with an HDAC inhibitor renders hsp90 inactive, thus impeding the DNA damage response that involves the ATR, CHK1, and BRCA1 proteins. Thus, HDAC inhibition creates an environment within cells that is similar to that seen in breast cancer cells with BRCA1 mutations.

“In simple terms, we are trying to cause a ‘BRCAness' so that you confer on triple-negative breast cancer cells the sensitivity to PARP inhibitors or platinum therapy seen when BRCA1 mutations are present,” Bhalla said.

The researchers examined the mechanism of action of HDAC inhibitors and determined that inhibition of HDAC3 specifically rendered hsp90 inactive and consequently inhibited repair of damaged DNA.

“The icing on the cake, so to speak, was that in addition to inhibiting the DNA damage response through depletion of DNA repair proteins, HDAC inhibitors induced DNA damage,” Bhalla said. “By using HDAC inhibitors, we were targeting the cancer two ways at once.”

Additionally, the researchers tested whether treatment with the HDAC inhibitors vorinostat or panobinostat would sensitize triple-negative breast cancer cells to PARP inhibition. When either of the HDAC inhibitors was combined with the PARP inhibitor ABT888, the result was the death of triple-negative breast cancer cells with or without BRCA1 mutation. Also, vorinostat treatment made the triple-negative breast cancer cells more susceptible to treatment with cisplatin.

Further validation of this study could lead to its findings having implications for women with triple-negative breast cancer and possibly for women with ovarian cancer. Ovarian cancer has a genetic make-up similar to that of triple-negative breast cancer.

“If you have a patient with triple-negative breast cancer who does not have a BRCA1 mutation, you could consider a clinical trial using an HDAC inhibitor in combination with a PARP inhibitor and cisplatin,” Bhalla said.

Bhalla has received clinical research support from Novartis Oncology, which makes panobinostat, the HDAC inhibitor used in the studies.

This study was presented at the CTRC-AACR San Antonio Breast Cancer Symposium, held December 4-8, 2012.
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