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HDAC inhibitors may cause BRCA1-like environment in triple-negative cells
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SAN ANTONIO — Exposing triple-negative breast cancer cells to HDAC inhibitor treatment rendered those cells unable to repair damaged DNA. This, in turn, may have made those cells sensitive to poly ADP ribose polymerase inhibitors and cisplatin therapy, which have demonstrated efficacy in breast cancer cells with BRCA1 mutations.
In a press conference at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, Kapil N. Bhalla, MD, chief of personalized cancer medicine at the University of Kansas Cancer Center in Kansas City, said breast cancer cells with poor DNA damage response and repair mechanisms may be sensitive to chemotherapy, which damages the DNA. He added that cells with homologous recombination DNA repair mechanism due to a BRCA1 mutation may be more sensitive to poly ADP ribose polymerase (PARP) inhibitors. Triple-negative tumors without BRCA1 mutations also may be more sensitive to PARP inhibitors and cisplatin.
Previous studies have indicated that proteins such as ATR, CHK1 and BRCA1 are necessary for a cell to respond to DNA damage. Heat shock protein 90 (Hsp90) manages these three proteins, according to Bhalla.
Other previous research from Bhalla and colleagues showed that treatment with an HDAC inhibitor renders Hsp90 inactive. Because of this, HDAC inhibition creates an environment similar to that induced by BRCA1 mutations.
“HDAC inhibitor treatment depletes DNA damage response and homologous recombination proteins leading to lethal synergy with PARP inhibitors and cisplatin,” Bhalla said. “These studies induce the need to test the efficacy of a treatment regimen that includes a PARP inhibitor combined with a pan-HDAC inhibitor and cisplatin against triple-negative breast cancers. They create more DNA damage.”
For more information:
Bhalla KN. #S3-7. Presented at: the 2012 CTRC-AACR San Antonio Breast Cancer Symposium; Dec. 4-8, 2012; San Antonio.
Disclosure: Bhalla reports receiving research support and honoraria from Novartis.