Molecular Regulation of Cell Cycle and Cell Cycle-Targeted Therapies in Head and Neck Squamous Cell Carcinoma (HNSCC)

Abstract

Head and neck squamous cell carcinomas (HNSCCs) are clinically challenging. The molecular mechanisms and genetic changes that drive HNSCCs have been studied with the aim of developing better therapeutic strategies involving novel molecular targets. Genomic studies have identified mutations in genes that mediate cell cycle, and key differences in cell cycle regulation differentiate both human papillomavirus (HPV)-associated and HPV-negative HNSCC cases from normal tissue. Some of these differences may nominate specific therapeutic targets and impact treatment response in HNSCC. For example, one of the most frequent cell cycle alterations in HPV (−) HNSCC is the disruption of the p53 (TP53) pathway (over 80% of tumors, based on data in TCGA and other studies), which is involved in cell cycle control, DNA damage signaling, and overall maintenance of genome stability. Other frequent alterations disrupt the cell cycle regulator CDKN2A (28% alteration frequency), which encodes p16, an inhibitor of cell cycle kinases CDK4 and CDK6, and alters expression of CCND1, resulting in inactivation of the tumor suppressor Rb. Other mutations found less commonly in patients target elements of the cell cycle checkpoint and DNA damage response machinery. Such observations and a growing recognition of the importance of cell cycle regulatory defects in HNSCC response to typically DNA-damaging chemotherapies and radiation therapy have rationalized the development of novel cell cycle-targeted therapies for HNSCCs. We here provide a general overview of the process of cell cycle control, cell cycle checkpoints, and how these are dysregulated in HNSCC and other cancers and discuss current cell cycle-targeted therapies in development and in clinical trials for HNSCC. The ultimate goal of these efforts is to develop new, potent therapeutic agents and to identify patient subpopulations that will be more responsive to cell cycle-targeted therapies.