ABSTRACT
Desmoplastic small round cell tumors (DSRCT) are a type of aggressive, pediatric sarcoma characterized by the EWSR1::WT1 fusion oncogene. Targeted therapies for DSRCT have not been developed, and standard multimodal therapy is insufficient, leading to a 5-year survival rate of only 15% to 25%. Here, we depleted EWSR1::WT1 in DSRCT and established its essentiality in vivo. Transcriptomic analysis revealed that EWSR1::WT1 induces unique transcriptional alterations compared with WT1 and other fusion oncoproteins and that EWSR1::WT1 binding directly mediates gene upregulation. The E-KTS isoform of EWSR1::WT1 played a dominant role in transcription, and it bound to the CCND1 promoter and stimulated DSRCT growth through the cyclin D-CDK4/6-RB axis. Treatment with the CDK4/6 inhibitor palbociclib successfully reduced growth in two DSRCT xenograft models. As palbociclib has been approved by the FDA for the treatment of breast cancer, these findings demonstrate the sensitivity of DSRCT to palbociclib and support immediate clinical investigation of palbociclib for treating this aggressive pediatric cancer. SIGNIFICANCE: EWSR1::WT1 is essential for desmoplastic small round cell tumors and upregulates the cyclin D-CDK4/6-RB axis that can be targeted with palbociclib, providing a targeted therapeutic strategy for treating this deadly tumor type.
Subject(s)
Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Desmoplastic Small Round Cell Tumor , Oncogene Proteins, Fusion , Piperazines , Pyridines , RNA-Binding Protein EWS , Xenograft Model Antitumor Assays , Animals , Humans , Mice , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/genetics , Desmoplastic Small Round Cell Tumor/genetics , Desmoplastic Small Round Cell Tumor/drug therapy , Desmoplastic Small Round Cell Tumor/pathology , Desmoplastic Small Round Cell Tumor/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Piperazines/pharmacology , Piperazines/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyridines/pharmacology , Pyridines/therapeutic use , RNA-Binding Protein EWS/genetics , RNA-Binding Protein EWS/metabolism , WT1 Proteins/genetics , WT1 Proteins/metabolism , Mice, Inbred NODABSTRACT
The Never in Mitosis Gene A (NIMA)-related kinases (NEKs) are a group of serine/threonine kinases that are involved in a wide array of cellular processes including cell cycle regulation, DNA damage repair response (DDR), apoptosis, and microtubule organization. Recent studies have identified the involvement of NEK family members in various diseases such as autoimmune disorders, malignancies, and developmental defects. Despite the existing literature exemplifying the importance of the NEK family of kinases, this family of protein kinases remains understudied. This report seeks to provide a foundation for investigating the role of different NEKs in malignancies. We do this by evaluating the 11 NEK family kinase gene expression associations with patients' overall survival (OS) from various cancers using the Kaplan-Meier Online Tool (KMPlotter) to correlate the relationship between mRNA expression of NEK1-11 in various cancers and patient survival. Furthermore, we use the Catalog of Somatic Mutations in Cancer (COSMIC) database to identify NEK family mutations in cancers of different tissues. Overall, the data suggest that the NEK family has varying associations with patient survival in different cancers with tumor-suppressive and tumor-promoting effects being tissue-dependent.
