SMARCA4 biology in alveolar rhabdomyosarcoma

Narendra Bharathy, Megan M. Cleary, Jin Ah Kim, Kiyo Nagamori, Kenneth A. Crawford, Eric Wang, Debarya Saha, Teagan P. Settelmeyer, Reshma Purohit, Damianos Skopelitis, Kenneth Chang, Jessica A. Doran, C. Ward Kirschbaum, Suriya Bharathy, Davis W. Crews, Matthew E. Randolph, Anthony N. Karnezis, Lisa Hudson-Price, Jyotsna Dhawan, Joel E. MichalekAlessio Ciulli, Christopher R. Vakoc, Charles Keller

Research output: Contribution to journalArticlepeer-review

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - 2022
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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