Abstract
ACY-241 is a novel, orally available and selective histone deacetylase (HDAC) 6 inhibitor in Phase 1b clinical development in multiple myeloma (NCT 02400242). Like the structurally related drug ACY-1215 (ricolinostat), ACY-241 has the potential for a substantially reduced side effect profile versus current nonselective HDAC inhibitor drug candidates due to reduced potency against Class I HDACs while retaining the potential for anticancer effectiveness. We now show that combination treatment of xenograft models with paclitaxel and either ricolinostat or ACY-241 significantly suppresses solid tumor growth. In cell lines from multiple solid tumor lineages, combination treatment with ACY-241 and paclitaxel enhanced inhibition of proliferation and increased cell death relative to either single agent alone. Combination treatment with ACY-241 and paclitaxel also resulted in more frequent occurrence of mitotic cells with abnormal multipolar spindles and aberrant mitoses, consistent with the observed increase of aneuploid cells. At the molecular level, multipolar mitotic spindle formation was observed to be NuMA-dependent and γ-tubulin independent, suggesting that treatment-induced multipolar spindle formation does not depend on centrosomal amplification. The significantly enhanced efficacy of ACY-241 plus paclitaxel observed here, in addition to the anticipated superior safety profile of a selective HDAC6 inhibitor versus pan-HDAC inhibitors, provides a strong rationale for clinical development of this combination in patients with advanced solid tumors.
Highlights
Paclitaxel is a chemotherapeutic agent approved for use in the treatment of multiple solid tumor types, including breast cancer, ovarian cancer, non-small cell lung cancer and Kaposi’s sarcoma [1,2,3]
Recent studies indicate that lower concentrations of paclitaxel, similar to levels observed within the tumors of treated patients, caused multipolar mitotic spindle formation, subsequently resulting in aberrant mitosis and cell death, which likely contributes to the anti-cancer efficacy of paclitaxel [8, 9]
Hyperacetylation of histone H3, a target of Class I histone deacetylase (HDAC), was only observed at doses above 1 μM. This result confirms that low exposures of ACY-241 result in selective inhibition of HDAC6, while higher exposures leads to inhibition of Class I HDAC isozymes
Summary
Paclitaxel is a chemotherapeutic agent approved for use in the treatment of multiple solid tumor types, including breast cancer, ovarian cancer, non-small cell lung cancer and Kaposi’s sarcoma [1,2,3]. Recent studies indicate that lower concentrations of paclitaxel, similar to levels observed within the tumors of treated patients, caused multipolar mitotic spindle formation, subsequently resulting in aberrant mitosis and cell death, which likely contributes to the anti-cancer efficacy of paclitaxel [8, 9] Consistent with this discovery, live cell imaging showed that paclitaxel treatment suppressed microtubule dynamic instability and induced multi-aster formation [10]. Microtubules are complex polymers that repeatedly undergo rapid and stochastic transitions between growth and contraction, enabling localized changes for specific physiologic purposes, for example, mitotic spindle formation during mitosis [11, 12] This instability is tightly regulated by multiple posttranslational modifications, including acetylation of lysine-40 of α-tubulin [13, 14], but is sensitive to microtubule disrupting agents, including paclitaxel and other taxane drugs [15, 16]. Amongst many known regulators of α-tubulin posttranslational modification, histone deacetylase (HDAC) 6 is the major deacetylase of lysine-40 [17]
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