CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets

Abstract

Sarcomas represent one of the most challenging tumor types to treat due to their diverse nature and our incomplete understanding of their underlying biology. Recent work suggests cyclin-dependent kinase (CDK) pathway activation is a powerful driver of sarcomagenesis. CDK proteins participate in numerous cellular processes required for normal cell function, but their dysregulation is a hallmark of many pathologies including cancer. The contributions and significance of aberrant CDK activity to sarcoma development, however, is only partly understood. Here, we describe what is known about CDK-related alterations in the most common subtypes of sarcoma and highlight areas that warrant further investigation. As disruptions in CDK pathways appear in most, if not all, subtypes of sarcoma, we discuss the history and value of pharmacologically targeting CDKs to combat these tumors. The goals of this review are to (1) assess the prevalence and importance of CDK pathway alterations in sarcomas, (2) highlight the gap in knowledge for certain CDKs in these tumors, and (3) provide insight into studies focused on CDK inhibition for sarcoma treatment. Overall, growing evidence demonstrates a crucial role for activated CDKs in sarcoma development and as important targets for sarcoma therapy.

Keywords: CDK inhibitors; cell cycle; cyclin-dependent kinase; retinoblastoma protein; sarcoma; therapeutics.

Figure 1

Overview of cell cycle cyclin-dependent kinase (CDK)-related signaling and regulation. (A) Several cell cycle CDKs inactivate RB1, promoting progression into S phase. RB1 binds and sequesters E2F transcription factors throughout G1. CDK4/6-cyclin D complexes phosphorylate RB1, priming it for subsequent phosphorylation by CDK2-cyclin A/E. Hyper-phosphorylation of RB1 causes release of E2F, enabling transcription of genes necessary for S phase and DNA synthesis. Two families of CDK inhibitors, CIP/KIP (p21/p27/p57) and INK4 (a/b/c/d), prevent RB1 phosphorylation; thereby halting cell cycle progression. (B) INK4 family members specifically inhibit CDK4 and CDK6 activity by preventing CDK-cyclin D complex formation. (C) CIP/KIP family members inhibit the various CDKs by binding the CDK-cyclin holoenzymes. Sites of post-translational modification in (B) CDK4, INK4, and cyclin D or (C) CDK2, p27KIP1, cyclin E that either promote (green) or inhibit (red) the function of each factor, as well as the modifying enzymes involved, are denoted.