Bioinformatic analysis of selinexor-induced gene expression in patient-derived-chordomas to reveal mechanisms of action leading to tumor growth inhibition.

Abstract

e23502 Background: Selinexor is a selective inhibitor of nuclear export that inhibits XPO1 from shuttling its cargo from the nucleus to the cytoplasm. This leads to accumulation of tumor suppressor proteins in the nucleus, activation of cell cycle checkpoints, cell cycle arrest and apoptosis in cancer cells. Chordomas are rare cancers emanating from the skull base and spine that originate from remnants of the notochord. Patients with chordomas have poor prognosis with limited treatment options. To investigate the in vivo efficacy and assess molecular effects of selinexor treatment in chordoma, two patient-derived xenograft (PDX) mouse models were tested. Methods: Murine chordoma PDX models of recurrent clival chordoma (SF8894) and metastatic sacral chordoma (CF466) were treated with selinexor (5mg/kg PO, 4x weekly). Tumor volume was monitored for 6 weeks of treatment, then excised tumors were used for immunohistochemistry (IHC) analysis and RNA sequencing. Results: Selinexor treatment significantly reduced the tumor volume of mice bearing CF466-derived tumors (5 mice/group; 57.6% reduction in volume compared to control; P = 0.031), and SF8894-derived tumors (4 mice/group; 76.2% reduction; P < 0.001). Differential gene expression between selinexor and vehicle treated samples showed significant differences in 428 genes and 156 genes in the CF466 and SF8894 tumors, respectively (adjusted P-value [Padj] < 0.01). In both models, XPO1 protein levels were markedly decreased and expression of the tumor suppressors TP53 (CF466: Padj = 1.4x10−17; SF8894: Padj = 0.002) and ARRDC3 (CF466: Padj = 2.2x10−72; SF8894: Padj = 2.9x10−12) were increased. In the CF466 chordoma model, selinexor reduced SOX9 (Padj = 1.6x10−18), SMAD4 (Padj = 0.019), and SHH (Padj = 0.028), which were confirmed to be reduced at the protein level by IHC. The SF8894 model showed reduction in EZH2 expression (Padj = 0.0012). Pathway analysis of both models showed activated TP53 signaling (CF466: z-score = 0.82; SF8894: z-score = 2.16) and apoptosis (CF466: P = 5.2x10−8; SF8894: P = 1.2x10−8). G2/M checkpoint regulators were upregulated in the CF466 model (z-score = 2.83). Conclusions: Selinexor treatment led to reduction in tumor growth in two PDX models of chordoma. Both models showed upregulation of TP53 signaling and apoptosis upon treatment, with downregulation of distinct oncogenic pathways. Further investigation of selinexor as a treatment option for chordoma is warranted.