HDAC Inhibitor plus PARP Inhibitor or Cisplatin Induce Apoptosis of Triple-Negative Breast Cancer Cells
Histone deacetylase (HDAC) inhibitors may have a future in the targeted treatment of triple-negative breast cancer, if the results of in vitro studies can be replicated clinically.
HDAC inhibitors are cytostatic agents that have been shown to limit the proliferation of tumor cells in culture. In the case of triple-negative tumors, research is showing that exposure to an HDAC inhibitor indirectly impairs the ability of these cells to repair damaged DNA, and at the same time it sensitizes them to 2 agents that are frequently used in the treatment of triple-negative disease—a PARP inhibitor and cisplatin (Platinol).
Kapil N. Bhalla, MD, FACP, Chief of Personalized Cancer Medicine at the University of Kansas Cancer Center in Kansas City, explained that the prospect for HDAC inhibitors in this tumor subtype arose from the likelihood that heat shock protein 90 (hsp90), the highly conserved and abundant cell chaperone, is involved in carcinogenesis.
Dr Bhalla and colleagues previously reported that treatment with an HDAC inhibitor renders hsp90 inactive, thereby impeding the DNA damage response that involves the ATR-BRCA1-Chk1 signaling pathway (these are hsp90 client proteins). HDAC inhibition creates an environment within cells that is not unlike that seen in breast cancer cells with BRCA1 mutations.
“In the present study, we determined that treatment with vorinostat [Zolinza] or panobinostat induced hyperacetylation and inhibition of chaperone function of nuclear hsp90, leading to proteasomal degradation and the depletion of ATR, Chk1, and BRCA1,” he said. This ultimately stopped the DNA repair process.
Dr Bhalla and colleagues also investigated whether the pan-HDAC inhibitors vorinostat or panobinostat could sensitize triple-negative breast cancer cells to PARP inhibition. They found that either agent, when given together with the PARP inhibitor ABT888, was a lethal combination to triple-negative cells, regardless of whether the cells contained the BRCA1 mutation.
These findings indicate that treatment with pan-HDAC inhibitors creates “BRCAness,” and that in combination with a PARP inhibitor or cisplatin, it synergistically induces apoptosis in triple-negative breast cancer cells.
“These studies support the rationale of testing the efficacy of a treatment regimen that includes a PARP inhibitor combined with a pan-HDAC inhibitor and cisplatin against triple-negative breast cancers,” Dr Bhalla noted.
Dr Bhalla foresees the clinical application of his research. “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,” he advised.