Data from Therapeutic Potential of NTRK3 Inhibition in Desmoplastic Small Round Cell Tumor

Abstract

<div>AbstractPurpose:<p>Desmoplastic small round cell tumor (DSRCT) is a highly lethal intra-abdominal sarcoma of adolescents and young adults. DSRCT harbors a t(11;22)(p13:q12) that generates the EWSR1-WT1 chimeric transcription factor, the key oncogenic driver of DSRCT. EWSR1-WT1 rewires global gene expression networks and activates aberrant expression of targets that together mediate oncogenesis. EWSR1-WT1 also activates a neural gene expression program.</p>Experimental Design:<p>Among these neural markers, we found prominent expression of neurotrophic tyrosine kinase receptor 3 (NTRK3), a druggable receptor tyrosine kinase. We investigated the regulation of NTRK3 by EWSR1-WT1 and its potential as a therapeutic target <i>in vitro</i> and <i>in vivo</i>, the latter using novel patient-derived models of DSRCT.</p>Results:<p>We found that EWSR1-WT1 binds upstream of <i>NTRK3</i> and activates its transcription. NTRK3 mRNA is highly expressed in DSRCT compared with other major chimeric transcription factor–driven sarcomas and most DSRCTs are strongly immunoreactive for NTRK3 protein. Remarkably, expression of <i>NTRK3</i> kinase domain mRNA in DSRCT is also higher than in cancers with <i>NTRK3</i> fusions. Abrogation of NTRK3 expression by RNAi silencing reduces growth of DSRCT cells and pharmacologic targeting of NTRK3 with entrectinib is effective in both <i>in vitro</i> and <i>in vivo</i> models of DSRCT.</p>Conclusions:<p>Our results indicate that EWSR1-WT1 directly activates NTRK3 expression in DSRCT cells, which are dependent on its expression and activity for growth. Pharmacologic inhibition of NTRK3 by entrectinib significantly reduces growth of DSRCT cells both <i>in vitro</i> and <i>in vivo</i>, providing a rationale for clinical evaluation of NTRK3 as a therapeutic target in DSRCT.</p></div>