The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma

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Hernández-García, Susana ; San-Segundo, Laura ; González-Méndez, Lorena ; Corchete, Luis A ; Misiewicz-Krzeminska, Irena ; Martín-Sánchez, Montserrat ; López-Iglesias, Ana-Alicia ; Algarín, Esperanza Macarena ; Mogollón, Pedro ; Díaz-Tejedor, Andrea ; Paíno, Teresa ; Tunquist, Brian ; Mateos, María-Victoria ; Gutiérrez, Norma C ; Díaz-Rodriguez, Elena ; Garayoa, Mercedes ; Ocio, Enrique M (2017)
  • Publisher: Ferrara Storti Foundation
  • Journal: volume 102, issue 12, pages 2,113-2,124 (issn: 0390-6078, eissn: 1592-8721)
  • Related identifiers: doi: 10.3324/haematol.2017.168666, pmc: PMC5709111
  • Subject: Plasma Cell Disorders | Dexamethasone | :MEDICINE [Research Subject Categories] | Multiple myeloma | Kinesin spindle protein inhibitor | BAK activation | Filanesib | Article | Pomalidomide | Monopolar spindles

[EN]Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor of this protein, has demonstrated activity in heavily pre-treated multiple myeloma patients. The aim of the work herein was to investigate the activity of filanesib in combination with pomalidomide plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. The ability of filanesib to enhance the activity of pomalidomide plus dexamethasone was studied in several in vitro and in vivo models. Mechanisms of this synergistic combination were dissected by gene expression profiling, immunostaining, cell cycle and short interfering ribonucleic acid studies. Filanesib showed in vitro, ex vivo, and in vivo synergy with pomalidomide plus dexamethasone treatment. Importantly, the in vivo synergy observed in this combination was more evident in large, highly proliferative tumors, and was shown to be mediated by the impairment of mitosis transcriptional control, an increase in monopolar spindles, cell cycle arrest and the induction of apoptosis in cells in proliferative phases. In addition, the triple combination increased the activation of the proapoptotic protein BAX, which has previously been associated with sensitivity to filanesib, and could potentially be used as a predictive biomarker of response to this combination. Our results provide preclinical evidence for the potential benefit of the combination of filanesib with pomalidomide and dexamethasone, and supported the initiation of a recently activated trial being conducted by the Spanish Myeloma group which is investigating this combination in relapsed myeloma patients. Array BioPharma, the Spanish ISCIII-FIS and FEDER, the Spanish RTICC, Spanish Association Against Cancer (AECC) and the Regional Council of Castilla y León (Consejería de Medicina y Educación).
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