The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma

Salah Eddine Lamhamedi-Cherradi, Mayinuer Maitituoheti, Brian A. Menegaz, Sandhya Krishnan, Amelia M. Vetter, Pamela Camacho, Chia Chin Wu, Hannah C. Beird, Robert W. Porter, Davis R. Ingram, Vandhana Ramamoorthy, Sana Mohiuddin, David McCall, Danh D. Truong, Branko Cuglievan, P. Andrew Futreal, Alejandra Ruiz Velasco, Nazanin Esmaeili Anvar, Budi Utama, Mark TitusAlexander J. Lazar, Wei Lien Wang, Cristian Rodriguez-Aguayo, Ravin Ratan, J. Andrew Livingston, Kunal Rai, A. Robert MacLeod, Najat C. Daw, Andrea Hayes-Jordan, Joseph A. Ludwig

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have direct clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.

Original languageEnglish (US)
Article number3057
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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