title: Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models.
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.
authors.affiliation: Acetylon Pharmaceuticals, Inc., Boston, MA 02210, USA.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Huang
authors.affiliation: Acetylon Pharmaceuticals, Inc., Boston, MA 02210, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Almeciga-Pinto
authors.affiliation: Acetylon Pharmaceuticals, Inc., Boston, MA 02210, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Jarpe
authors.affiliation: Acetylon Pharmaceuticals, Inc., Boston, MA 02210, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: van Duzer
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.affiliation: Acetylon Pharmaceuticals, Inc., Boston, MA 02210, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Acetylon Pharmaceuticals, Inc., Boston, MA 02210, USA.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Jones
authors.affiliation: Acetylon Pharmaceuticals, Inc., Boston, MA 02210, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Quayle
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D014404:Tubulin; D017239:Paclitaxel
keywords: HDAC; mitotic spindle; paclitaxel; solid tumors