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

Abstract

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.

Drug Targeting of Genomic Instability in Multiple Myeloma

“…In this study, low levels of alpha-1 acid glycoprotein, an acute-phase protein which can bind filanesib, was reported to be a useful biomarker that correlated with clinical response (Shah et al, 2017). Based on encouraging results in preclinical in vivo studies in which filanesib was combined with pomalidomide, the anti-myeloma efficacy of the triplet combination of filanesib, pomalidomide and dexamethasone was evaluated both in vitro and in vivo (Hernández-García et al, 2017). This combination revealed strong synergy and resulted in an increase in the number of monopolar spindles and level of BAX, cell cycle arrest in mitosis and subsequent apoptosis (Hernández-García et al, 2017).…”

“…Based on encouraging results in preclinical in vivo studies in which filanesib was combined with pomalidomide, the anti-myeloma efficacy of the triplet combination of filanesib, pomalidomide and dexamethasone was evaluated both in vitro and in vivo (Hernández-García et al, 2017). This combination revealed strong synergy and resulted in an increase in the number of monopolar spindles and level of BAX, cell cycle arrest in mitosis and subsequent apoptosis (Hernández-García et al, 2017). In light of these results, the Spanish Myeloma Group conducted a clinical trial (POMDEFIL) of this triplet combination in RRMM patients to assess safety and efficacy.…”

Overexpression of kinesin superfamily members as prognostic biomarkers of breast cancer

“…Ispinesib, a KIF11targeted inhibitor, was the first KIF-inhibitor that was evaluated both safety and efficacy in breast cancer in phase I clinical study [30]. Other KIF-targeted drugs further tested in various cancers by clinical trials including KIF11 inhibitors (litronesib [31,32], filanesib [33][34][35], SB-743921 [36], AZD4877 [37]), KIF5C inhibitors (Lidocaine and Tetracaine [38]) and KIFC1 inhibitors (AZ82 and SR31527 [39,40]). However, limited efficacy was seen in all inhibitors reported.…”

Drug targets and resistance mechanisms in multiple myeloma

“…Filanesib (ARRY-520), a kinesin motor protein inhibitor showed in vivo synergy with pomalidomide plus dexamethasone treatment [110] . A phase I/II study of filanesib alone and in combination with low-dose dexamethasone in relapsed/refractory MM showed a manageable safety profile and encouraging activity in heavily pre-treated patients [111] .…”