Abstract 501: Inhibition of exportin 1 (XPO1) by selinexor (KPT-330) synergistically suppresses growth of neuroblastoma in combination with doxorubicin or bromodomain inhibition

Abstract

Background: Neuroblastoma is a childhood malignancy of the peripheral nervous system, and most patients with high-risk disease are not cured. Exportin 1 (XPO1; Chromosome Region Maintenance 1 Protein Homolog, CRM1) is the sole nuclear exporter of TP53, FOXO1, RB1, CDKN1A, and other critical tumor suppressor proteins (TSPs) and is abundantly expressed in high-risk neuroblastoma. In addition, these major tumor suppressor proteins are rarely mutated in neuroblastoma, and thus inhibition of XPO1 is a rational anti-neuroblastoma strategy. The orally bioavailable drug selinexor (KPT-330) is a selective inhibitor of nuclear export that forms a slowly reversible covalent bond to XPO1 and inhibits XPO1-mediated nuclear export. We previously showed that selinexor showed cytotoxicity with sensitivity independent of MYCN amplification status resulting in decreased Myc family protein levels and activation of apoptotic pathways. In addition, flank xenograft models and mouse models of metastatic disease showed significant tumor growth inhibition across multiple neuroblastoma cell lines. Methods: A time course microarray experiment was performed to discover temporal effects across four neuroblastoma cell lines following exposure to selinexor. Models were selected at the extremes of drug sensitivity and expression profiles were generated after 8 and 24 hours of selinexor exposure. Results: The intersection of linear and K-clustering methods revealed genes that followed a consecutively increasing or decreasing profile with respect to time. There were 4 genes in common to all cell lines, 29 genes across 3 cell lines, and 88 between the two most sensitive cell lines. Based off these observations, MAST3, GPRIN1, SMACRD2, and SENP5 were further explored in a larger cohort of neuroblastoma cell lines. In addition, gene set enrichment analysis revealed a doxorubicin-sensitivity expression profile in more resistant lines after exposure to selinexor. The combination of selinexor and doxorubicin resulted in synergistic increases in cell death. Chromatin remodeling genes were significantly disrupted by selinexor across all models, and the combination of selinexor and the bromodomain inhibitor JQ1 resulted in decreased MYCN protein levels and also showed evidence of synergy in vitro. Conclusions: Expression profiling of neuroblastoma cell lines following selinexor exposure has uncovered candidate biomarkers of activity and sensitivity. The potent synergy with other chemotherapeutic agents provides evidence for rational drug combinations. Selinexor is currently in pediatric phase 1 trials and has the potential to be rapidly translated into a novel therapeutic approach for children with neuroblastoma. Citation Format: Pietro J. Ranieri, Rebecca Trillo, Yosef Landesman, William Senapedis, Dilara McCauley, Sharon Shacham, Michael Kauffman, John M. Maris, Edward F. Attiyeh. Inhibition of exportin 1 (XPO1) by selinexor (KPT-330) synergistically suppresses growth of neuroblastoma in combination with doxorubicin or bromodomain inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 501. doi:10.1158/1538-7445.AM2015-501