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.

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.

The Never-in-Mitosis A-Related Kinase (NEK) family is an important, yet largely understudied, family of protein kinases involved in the regulation of a variety of critical cellular processes. Consequently, dysregulation of NEK function has been linked to the etiology and progression of several disorders, including cancer, ciliopathies, neurodegenerative disorders, inflammatory disorders, and other pervasive diseases. In this review, we have summarized recent findings to provide an overview of the NEK family and their diverse functions within various cellular contexts. In parallel, we have highlighted the emerging roles of NEK family members in human health, identifying potential therapeutic targets within the NEK family and exploring their potential for future clinical applications. Finally, we have addressed ongoing challenges and emerging research directions in this rapidly evolving field, aiming to pave the way for future discoveries and innovations.

EWSR1::WT1 Downregulated Pathways

EWSR1::WT1 Downregulated Pathways

EWSR1::WT1 Upregulated Pathways