Abstract
Histone deacetylase inhibitors (HDACi) are novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with multiple myeloma (MM). Although HDACi have demonstrable synergy when combined with proteasome inhibitors (PIs), recent evidence indicates that combination of HDACi and PI is beneficial only in a subset of patients with advanced MM, clearly indicating that other rational combinations should be explored. In this context we hypothesized that understanding the molecular signature associated with inherent resistance to HDACi would provide a basis for the identification of therapeutic combinations with improved clinical efficacy. Using human myeloma cell lines (HMCL) categorized as sensitive, intermediate or resistant to HDACi, gene expression profiling (GEP) and gene ontology enrichment analyses were performed to determine if a genetic signature associated with inherent resistance to HDACi-resistance could be identified. Correlation of GEP to increasing or decreasing sensitivity to HDACi indicated a unique 35-gene signature that was significantly enriched for two pathways – regulation of actin cytoskeleton and protein processing in endoplasmic reticulum. When HMCL and primary MM samples were treated with a combination of HDACi and agents targeting the signaling pathways integral to the actin cytoskeleton, synergistic cell death was observed in all instances, thus providing a rationale for combining these agents with HDACi for the treatment of MM to overcome resistance. This report validates a molecular approach for the identification of HDACi partner drugs and provides an experimental framework for the identification of novel therapeutic combinations for anti-MM treatment.
Highlights
Histone deacetylase inhibitors (HDACi) are epigenetic modifying agents that initiate a myriad of cellular responses impeding both the proliferation and viability of MM cells
HDACi were able to induce varying levels of proliferation inhibition in human myeloma cell lines (HMCL), with U266 being the most resistant, followed by OPM2. To determine if this pattern of response could be re-capitulated in a cell death assay, a larger cohort of nine HMCL was treated with three HDACi
The proportion of cell death induced by the three inhibitors was similar in all HMCL tested indicating that cell death induced by HDACi, whether a pan-HDACi or a Class I specific inhibitor, is orchestrated by similar mechanism(s)
Summary
Histone deacetylase inhibitors (HDACi) are epigenetic modifying agents that initiate a myriad of cellular responses impeding both the proliferation and viability of MM cells. A number of genes that were differentially regulated between the sensitive, intermediate and resistant HMCL, including FGF9, F2R, ELF3, OPN3 (opsin-3), RGS12 and KIF4A (kinesin family member 4A) and are known to be associated with the actin cytoskeleton pathway are represented in the signaling pathway (Figure 4).
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