Synapse - Therapeutic potential of NTRK3 inhibition in desmoplastic small round cell tumor

Therapeutic potential of NTRK3 inhibition in desmoplastic small round cell tumor Journal Article

Authors:	Ogura, K.; Somwar, R.; Hmeljak, J.; Magnan, H.; Benayed, R.; Momeni Boroujeni, A.; Bowman, A. S.; Mattar, M. S.; Khodos, I.; de Stanchina, E.; Jungbluth, A.; Asher, M.; Odintsov, I.; Hartono, A. B.; LaQuaglia, M. P.; Slotkin, E.; Pratilas, C. A.; Lee, S. B.; Spraggon, L.; Ladanyi, M.
Article Title:	Therapeutic potential of NTRK3 inhibition in desmoplastic small round cell tumor
Abstract:	Purpose: 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. Experimental Design: 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 in vitro and in vivo, the latter using novel patient-derived models of DSRCT. Results: We found that EWSR1-WT1 binds upstream of NTRK3 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 NTRK3 kinase domain mRNA in DSRCT is also higher than in cancers with NTRK3 fusions. Abrogation of NTRK3 expression by RNAi silencing reduces growth of DSRCT cells and pharmacologic targeting of NTRK3 with entrectinib is effective in both in vitro and in vivo models of DSRCT. Conclusions: 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 in vitro and in vivo, providing a rationale for clinical evaluation of NTRK3 as a therapeutic target in DSRCT.
Keywords:	protein; fusion; transcripts; target; ros1; entrectinib; alk inhibitor; pan-trk
Journal Title:	Clinical Cancer Research
Volume:	27
Issue:	4
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2021-02-15
Start Page:	1184
End Page:	1194
Language:	English
ACCESSION:	WOS:000620168400032
DOI:	10.1158/1078-0432.Ccr-20-2585
PROVIDER:	wos
PUBMED:	33229458
PMCID:	PMC8212565
Notes:	Article -- Source: Wos