HDAC Inhibition Appears to Sensitize Triple-Negative Breast Cancer Cells to Certain Treatments

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Preliminary research suggests that in-vitro exposure to an HDAC inhibitor may sensitize triple-negative breast cancer cells to treatment with a PARP inhibitor and cisplatin.

Kapil N. Bhalla, MD

Preliminary research suggests that in-vitro exposure to an HDAC inhibitor may sensitize triple-negative breast cancer cells to treatment with a PARP inhibitor and cisplatin, according to research presented at the 35th San Antonio Breast Cancer Symposium.

HDAC inhibitor exposure appears to indirectly cause DNA damage and impair the cells’ ability to repair damaged DNA, thus sensitizing the cells to these two treatments. These effects mimic those in BRCA1 mutated breast cancer cells (i.e., “BRCAness”).

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

DNA repair is essential for survival of certain tumor cells. Previous research has found that proteins such as ATR, CHK1, and BRCA1 are key elements of a cell’s response to DNA damage and subsequent repair of the damage. These three proteins are chaperoned by heat shock protein 90 (hsp90).

Previous work by Bhalla and colleagues showed that treatment with an HDAC inhibitor renders hsp90 inactive, thus impeding the DNA damage response involving the three aforementioned proteins. In this way, HDAC inhibition creates an intracellular environment that mimics that seen in breast cancer with BRCA mutations.

“In simple terms, with HDAC inhibition, we are trying to cause a ‘BRCAness’ to confer on triple-negative breast cancer cells the sensitivity to PARP inhibition or platinum therapy seen in the presence of BRCA1 mutations,” Bhalla said.

Their studies showed that inhibition of HDAC3 specifically rendered hsp90 inactive, consequently inhibiting 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 in two ways at once.”

Bhalla and colleagues also analyzed whether treatment with the HDAC inhibitors vorinostat or panobinostat would sensitize triple-negative breast cancer cells to PARP inhibition. Combining either of the HDAC inhibitors with the PARP inhibitor ABT888 resulted in the death of triple-negative breast cancer cells with or without the BRCA1 mutation. Additionally, vorinostat treatment made the triple-negative breast cancer cells more susceptible to treatment with cisplatin.

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“These findings indicate that treatment with pan-HDAC inhibitors vorinostat or panibostat creates ‘BRCAness,' and in combination with a PARP inhibitor or cisplatin synergistically induces apoptosis in human triple-negative breast cancer cells,” Bhalla said.

If these findings are confirmed by further study, Bhalla said that they could have treatment implications for women with triple-negative breast cancer and potentially for ovarian cancer, which has a similar genetic makeup 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 with an HDAC inhibitor in combination with a PARP inhibitor and cisplatin,” Bhalla said.

Bhalla KN, Rao R, Sharma P, et al. Treatment with histone deacetylase inhibitors creates 'BRCAness' and sensitizes human triple negative breast cancer cells to PARP inhibitors and cisplatin. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract S3-7.


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