Using isogenic cell lines, researchers performed a study to examine resistance or sensitivity of cells to histone deacetylase (HDAC) inhibitors, in an attempt to understand this agent’s potential in treating bortezomib-resistant multiple myeloma (MM), with results suggesting the possibility of combination approaches to treatment using panobinostat. Results of the study were published in the journal Cancer Drug Resistance.

Bortezomib is a proteasome inhibitor that is often used in frontline therapy for MM, but resistance or refractoriness can occur with this agent. Panobinostat is an HDAC inhibitor, which is a class of agents approved in cases of relapsed or refractory MM. “However, panobinostat’s specific molecular mechanism of action is still largely unknown given its broad inhibitory effects on HDACs,” the researchers wrote in their report. Panobinostat is also associated with certain toxicities and the researchers indicated that improved understanding of HDAC-based therapies could potentially aid in refining treatment strategies.

This study made use of bortezomib-resistant and bortezomib-sensitive models to establish profiles of HDAC expression and to evaluate HDAC inhibitor-induced expression patterns of HDAC proteins in resistant and sensitive myeloma cells. Cells were evaluated for HDAC expression after treatment with either panobinostat or another HDAC inhibitor, such as vorinostat.


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Cells were also treated either pharmacologically or with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 treatment to reduce expression of genes for various proteins of the HDAC family to measure the effects of knockdowns.

The researchers found evidence of differing roles for HDAC6 and HDAC7 proteins in the regulation of cell death in bortezomib-resistant cells. In bortezomib-resistant myeloma cell lines, the HDAC6 protein was found to show slightly higher expression, compared with wild-type cells. Conversely, expression of HDAC7 was significantly downregulated in bortezomib-resistant cells. Treatment with panobinostat further enhanced downregulation of HDAC7, while vorinostat did not show this effect. In cells treated with CRISPR/Cas9 to inhibit HDAC7 expression, cell growth was inhibited.

Panobinostat showed activity in bortezomib-resistant cell lines in terms of cell death, but vorinostat did not. Panobinostat treatment also significantly upregulated HDAC6 expression in both bortezomib-resistant cells and in wild-type cells, while vorinostat did not.

For cells treated pharmacologically to inhibit HDAC6 expression, greater cell death occurred with treatment with panobinostat, indicating a potential synergy between panobinostat and HDAC6-inhibitor activity in promotion of cell death. This result led the researchers to suggest the possibility of a route to de-escalation of panobinostat therapy while treating with an HDAC6 inhibitor, potentially enabling a reduction in toxicities with panobinostat.

“In summary, our data showed heterogeneous expression of HDACs between bortezomib-sensitive and resistant cells; however, HDAC7 downregulation in resistant lines was striking and consistent across models,” the researchers wrote. They concluded that HDACs in MM show complex functions and considered the study’s results suggestive of a potential combination approaches using panobinostat in treatment of MM.

Reference

Cheng T, Kiser K, Grasse L, et al. Expression of histone deacetylase (HDAC) family members in bortezomib-refractory multiple myeloma and modulation by panobinostat. Cancer Drug Resist. 2021;4(4):888-902. doi:10.20517/cdr.2021.44