TY - JOUR
T1 - SMARCA4 biology in alveolar rhabdomyosarcoma
AU - Bharathy, Narendra
AU - Cleary, Megan M.
AU - Kim, Jin-Ah
AU - Nagamori, Kiyo
AU - Crawford, Kenneth A.
AU - Wang, Eric
AU - Saha, Debarya
AU - Settelmeyer, Teagan P.
AU - Purohit, Reshma
AU - Skopelitis, Damianos
AU - Chang, Kenneth
AU - Doran, Jessica A.
AU - Kirschbaum, C. Ward
AU - Bharathy, Suriya
AU - Crews, Davis W.
AU - Randolph, Matthew E.
AU - Karnezis, Anthony N.
AU - Hudson-Price, Lisa
AU - Dhawan, Jyotsna
AU - Michalek, Joel E.
AU - Ciulli, Alessio
AU - Vakoc, Christopher R.
AU - Keller, Charles
N1 - This study was funded by Braver Stronger Smarter Foundation, Maddie’s Promise Foundation and by NIH grants R01CA189299 & R01CA258720. The ACBI-1 PROTAC degrader was developed with funding support to the Ciulli Laboratory by Boehringer Ingelheim. CRV was supported by the Pershing Square Sohn Cancer Research Alliance, Northwell Health Translational Research Award, The Christina Renna Foundation, The Clark Gillies Foundation, The Friends of T.J. Foundation, The Michelle Paternoster Foundation, and a grant from National Cancer Institute (CA2455859). DS was supported by the Indo-U.S. GETin program from Department of Biotechnology (DBT), Govt. of India and Indo-U.S. Science and Technology Forum (IUSSTF).
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/3/10
Y1 - 2022/3/10
N2 - 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.
AB - 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.
KW - Paediatric cancer
KW - Proteomics
UR - http://www.scopus.com/inward/record.url?scp=85123827905&partnerID=8YFLogxK
U2 - 10.1038/s41388-022-02205-0
DO - 10.1038/s41388-022-02205-0
M3 - Article
C2 - 35094009
VL - 41
SP - 1647
EP - 1656
JO - Oncogene
JF - Oncogene
SN - 0950-9232
ER -
