Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology.

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ICR Authors

Jones, Robin
 Huang, Paul

Authors

Rasmussen, SV
Jin, JX
Bickford, LR
Woods, AD
Sahm, F
Crawford, KA
Nagamori, K
Goto, H
Torres, KE
Sidoni, A
Rudzinski, ER
Thway, K
Jones, RL
Ciulli, A
Wright, H
Lathara, M
Srinivasa, G
Kannan, K
Huang, PH
Grünewald, TGP
Berlow, NE
Keller, C

Document Type

Journal Article

Date

2022-07-01

Date Accepted

2022-06-17

Abstract

BACKGROUND: Metastatic epithelioid sarcoma (EPS) remains a largely unmet clinical need in children, adolescents and young adults despite the advent of EZH2 inhibitor tazemetostat. METHODS: In order to realise consistently effective drug therapies, a functional genomics approach was used to identify key signalling pathway vulnerabilities in a spectrum of EPS patient samples. EPS biopsies/surgical resections and cell lines were studied by next-generation DNA exome and RNA deep sequencing, then EPS cell cultures were tested against a panel of chemical probes to discover signalling pathway targets with the most significant contributions to EPS tumour cell maintenance. RESULTS: Other biologically inspired functional interrogations of EPS cultures using gene knockdown or chemical probes demonstrated only limited to modest efficacy in vitro. However, our molecular studies uncovered distinguishing features (including retained dysfunctional SMARCB1 expression and elevated GLI3, FYN and CXCL12 expression) of distal, paediatric/young adult-associated EPS versus proximal, adult-associated EPS. CONCLUSIONS: Overall results highlight the complexity of the disease and a limited chemical space for therapeutic advancement. However, subtle differences between the two EPS subtypes highlight the biological disparities between younger and older EPS patients and emphasise the need to approach the two subtypes as molecularly and clinically distinct diseases.

Citation

Clinical and Translational Medicine, 2022, 12 (7), pp. e961 -

DOI

10.1002/ctm2.961

URI

https://repository.icr.ac.uk/handle/internal/5236

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Clinical and Translational Medicine

Publisher

JOHN WILEY & SONS LTD

ISSN

2001-1326

eISSN

2001-1326
2001-1326

Collections

Cancer Biology

Research Team

Mol and Systems Oncology

Notes