Overcoming inherent resistance to histone deacetylase inhibitors in multiple myeloma cells by targeting pathways integral to the actin cytoskeleton

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.

Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors

“…Previous reports have suggested that various mechanisms such as increased drug efflux, target overexpression and/or desensitization, chromatin/epigenetic alterations, increased antioxidant expression, and the activation of prosurvival signaling underlie HDAC inhibitor resistance [25]. Recently, constitutive activation of STAT proteins has been reported to predict vorinostat resistance [32], and targeting signaling pathways associated with the actin cytoskeleton has been reported to rescue multiple myeloma cells from HDAC inhibitor resistance [33]. In addition, a recent study identified 9 genes associated with the response of HDAC inhibitors in NSCLC cells; of these, NQO1, SEC23A, and PSME2 were closely associated with drug activity [20].…”

A Synergistic Anti-Cancer FAK and HDAC Inhibitor Combination Discovered by a Novel Chemical-Genetic High-Content Phenotypic Screen

“…These changes undoubtedly will cause cancer cells undue stress, and it may be that FAK is a key component of the pathways that mitigate that stress and permit cancer cell survival. In this regard, we note that cell shape (the regulation of which FAK contributes to via well-recognized effects on actin and adhesion networks) can alter histone acetylation (26) and that gene expression profiling of HDAC inhibitor resistance in human myeloma cell lines is reported to involve actin cytoskeleton-associated genes, and FAK itself, as part of a resistance gene signature (27). This supports the link that we have identified here between the regulation of the cellular epigenetic state by HDAC activity and FAK signaling, revealing a co-dependency in multiple cancer cell lines.…”

HDAC5–LSD1 axis regulates antineoplastic effect of natural HDAC inhibitor sulforaphane in human breast cancer cells

“…Several studies indicated that inherent resistance of HDACi was commonly observed in clinical trials of breast cancer patients. 44–48 However, the mechanism of HDACi resistance in breast cancer is still unclear. Based on the findings from our work, we speculate that enhanced HDAC5 expression in response to treatment with conventional HDACi could contribute to refractoriness to HDACi therapy.…”