2024-03-28T21:06:49Zhttps://gredos.usal.es/oai/requestoai:gredos.usal.es:10366/1358312024-01-30T08:40:30Zcom_10366_4577com_10366_4576com_10366_3823col_10366_4578
2018-01-08T18:53:23Z
urn:hdl:10366/135831
The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma
Hernández-García, Susana
San-Segundo, Laura
González-Méndez, Lorena
Corchete Sánchez, Luis Antonio
Misiewicz-Krzeminska, Irena
Martín-Sánchez, Montserrat
López-Iglesias, Ana-Alicia
Algarín, Esperanza Macarena
Mogollón Arroyo, Pedro
Díaz-Tejedor, Andrea
Paíno Gómez, María Teresa
Tunquist, Brian
Mateos Manteca, María Victoria
Gutiérrez Gutiérrez, Norma Carmen
Díaz-Rodriguez, Elena
Garayoa Berrueta, Mercedes
Ocio San Miguel, Enrique M.
MEDICINE
Filanesib
Kinesin spindle protein inhibitor
Pomalidomide
Dexamethasone
Monopolar spindles
BAK activation
Multiple myeloma
[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.
2018-01-08T18:53:23Z
2018-01-08T18:53:23Z
2017-12
info:eu-repo/semantics/article
Haematologica December 2017 102: 2113-2124
Print ISSN 0390-6078
Online ISSN 1592-8721
PubMed 28860344
http://hdl.handle.net/10366/135831
10.3324/haematol.2017.168666
eng
Regional Council of Castilla y León, Consejería de Educación (FIC335U14)
ISCIII-FIS, PI 15/00067
ISCIII-FIS, PI 15/02156
Spanish RTICC, RD12/0036/0058
AECC, GCB120981SAN
Regional Council of Castilla y León, Consejería de Sanidad (GRS 1029/A/14)
Regional Council of Castilla y León, Consejería de Sanidad (GRS 1175/A/15)
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivs 4.0 International
Ferrara Storti Foundation