Novel patient-derived models of desmoplastic small round cell tumor confirm a targetable dependency on ERBB signaling.

Abstract

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered preclinical therapeutic studies on this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies. We describe four DSRCT cell lines and one patient-derived xenograft model. Transcriptomic, proteomic and biochemical profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Antagonizing EGFR function with shRNAs, small-molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited proliferation of DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for evaluating EGFR antagonists in patients with DSRCT. This article has an associated First Person interview with the joint first authors of the paper.

• Authors: Roger S Smith, Igor Odintsov, Zebing Liu, Allan Jo-Weng Lui, Takuo Hayashi, Morana Vojnic, Yoshiyuki Suehara, Lukas Delasos, Marissa S Mattar, Julija Hmeljak, Hillary A Ramirez, Melissa Shaw, Gabrielle Bui, Alifiani B Hartono, Eric Gladstone, Siddharth Kunte, Heather Magnan, Inna Khodos, Elisa De Stanchina, Michael P La Quaglia, Jinjuan Yao, Marick Laé, Sean B Lee, Lee Spraggon, Christine A Pratilas, Marc Ladanyi, Romel Somwar
• Journal: Disease models & mechanisms (Dis Model Mech) Vol. 15 Issue 1 (01 01 2022) ISSN: 1754-8411 [Electronic] England
• PMID: 34841430 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022. Published by The Company of Biologists Ltd.

Chemical References

• Oncogene Proteins, Fusion
• WT1 Proteins

Topics

• Animals
• Desmoplastic Small Round Cell Tumor (drug therapy, genetics, pathology)
• Humans
• Mice
• Oncogene Proteins, Fusion (genetics, metabolism)
• Oncogenes
• Proteomics
• WT1 Proteins (genetics, metabolism, therapeutic use)