RUNX2 inhibition disrupts a PAX3::FOXO1-RUNX2 feed-forward loop and dismantles oncogenic gene programs in fusion-positive rhabdomyosarcoma.

ABSTRACT: Fusion-positive rhabdomyosarcoma is an aggressive pediatric cancer of skeletal muscle lineage, with a 5-year overall survival of <30% for high-risk disease, and <8% when metastatic. The PAX3::FOXO1 fusion gene, resulting from t(2:13), is a signature driver of fusion-positive rhabdomyosarcoma, but similar to other transcription-factor based fusion genes in other cancers, not currently pharmacologically tractable. To identify novel druggable proteins in fusion-positive rhabdomyosarcoma tumor tissue and cell lines, we performed mRNA-seq of RMS patient tumors and utilizing the human FP-RMS cell lines Rh30 and Rh4, found that the RUNX2 transcription factor was the top druggable dependency. In vitro loss of function studies using genetic (RNAi) or pharmacologic (small molecu

SUBMITTER: Mendes EA 

PROVIDER: S-EPMC12330556 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature