The Role of CDK Pathway Dysregulation and Its Therapeutic Potential in Soft Tissue Sarcoma

Abstract

Soft tissue sarcomas (STSs) are tumors that are challenging to treat due to their pathologic and molecular heterogeneity and their tumor biology that is not yet fully understood. Recent research indicates that dysregulation of cyclin-dependent kinase (CDK) signaling pathways can be a strong driver of sarcogenesis. CDKs are enzyme forms that play a crucial role in cell-cycle control and transcription. They belong to the protein kinases group and to the serine/threonine kinases subgroup. Recently identified CDK/cyclin complexes and established CDK/cyclin complexes that regulate the cell cycle are involved in the regulation of gene expression through phosphorylation of critical components of transcription and pre-mRNA processing mechanisms. The current and continually growing body of data shows that CDKs play a decisive role in tumor development and are involved in the proliferation and growth of sarcoma cells. Since the abnormal expression or activation of large numbers of CDKs is considered to be characteristic of cancer development and progression, dysregulation of the CDK signaling pathways occurs in many subtypes of STSs. This review discusses how reversal and regulation can be achieved with new therapeutics and summarizes the current evidence from studies regarding CDK modulation for STS treatment.

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“…Cyclin-dependent kinase 2 (CDK-2), a tyrosine kinase, has been shown to exhibit significant regulation of cell cycle progression and transition. It plays crucial roles in gene transcription, phosphorylation of cell cycle proteins, and DNA replication [165]. Numerous studies in the field of scientific research have shown the efficacy of CDK-2 inhibitors in conferring advantageous outcomes in the context of several malignancies, including breast cancer, colorectal cancer, and melanoma [166][167][168].…”

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“…The comprehensive genomic analysis via The Cancer Genome Atlas (TCGA) has shown that approximately one quarter of all sarcomas harbor genetic alterations in the Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) - Cyclin D (CCND) - CDK4 - retinoblastoma (RB) axis ( 15 , 16 ), providing strong rationale for targeting this crucial pathway in sarcomas. Hence, better understanding of the role of CDKs in cell biology and cancer, might provide novel avenues of treatment for advanced BSTS ( 14 , 17 ).…”