LAUSR

Simple Summary This review provides an overview of clinical features and current therapies in children, adolescents, and young adults (AYA) with sarcoma. It highlights the basic and clinical findings on the cyclin-dependent kinases 4 and 6 (CDK4/6) cell cycle regulatory pathway in the context of the precision medicine-based molecular profiles of the three most common types of pediatric and AYA sarcomas—osteosarcoma (OS), rhabdomyosarcoma (RMS), and Ewing sarcoma (EWS). Abstract Despite improved therapeutic and clinical outcomes for patients with localized diseases, outcomes for pediatric and AYA sarcoma patients with high-grade or aggressive disease are still relatively poor. With advancements in next generation sequencing (NGS), precision medicine now provides a strategy to improve outcomes in patients with aggressive disease by identifying biomarkers of therapeutic sensitivity or resistance. The integration of NGS into clinical decision making not only increases the accuracy of diagnosis and prognosis, but also has the potential to identify effective and less toxic therapies for pediatric and AYA sarcomas. Genome and transcriptome profiling have detected dysregulation of the CDK4/6 cell cycle regulatory pathway in subpopulations of pediatric and AYA OS, RMS, and EWS. In these patients, the inhibition of CDK4/6 represents a promising precision medicine-guided therapy. There is a critical need, however, to identify novel and promising combination therapies to fight the development of resistance to CDK4/6 inhibition. In this review, we offer rationale and perspective on the promise and challenges of this therapeutic approach.