Targeting NEDDylation as a Novel Approach to Improve the Treatment of Head and Neck Cancer

Simple Summary Head and neck cancer is a complex and heterogeneous disease that affects nearly 900,000 individuals every year. Despite this, very few treatment options exist, particularly for patients diagnosed with late-stage disease. Currently approved therapies for head and neck tumors display limited anticancer activity, which highlights the need for more effective treatment options. In this review, we discuss an exciting new class of drugs that inhibit the NEDDylation pathway. NEDDylation is a protein modification pathway which affects the appropriate degradation of a wide variety of targets. NEDDylation is often hyperactivated in head and neck cancers and, thus, makes for a potential therapeutic target. To date, several compounds have been developed to block NEDDylation including pevonedistat (MLN4924) and TAS4464. Inhibition of NEDDylation has shown promising results in a variety of head and neck cancer cell lines, animal models, and early stage clinical trials. This review will summarize the mechanisms of action of existing NEDDylation inhibitors and their status in clinical development. Head and neck cancer is diagnosed in nearly 900,000 new patients worldwide each year. Despite this alarming number, patient outcomes, particularly for those diagnosed with late-stage and human papillomavirus (HPV)-negative disease, have only marginally improved in the last three decades. New therapeutics that target novel pathways are desperately needed. NEDDylation is a key cellular process by which NEDD8 proteins are conjugated to substrate proteins in order to modulate their function. NEDDylation is closely tied to appropriate protein degradation, particularly proteins involved in cell cycle regulation, DNA damage repair, and cellular stress response. Components of the NEDDylation pathway are frequently overexpressed or hyperactivated in many cancer types including head and neck cancer, which contribute to disease progression and drug resistance. Therefore, targeting NEDDylation could have a major impact for malignancies with alterations in the pathway, and this has already been demonstrated in preclinical studies and clinical trials. Here, we will survey the mechanisms by which aberrant NEDDylation contributes to disease pathogenesis and discuss the potential clinical implications of inhibiting NEDDylation as a novel approach for the treatment of head and neck cancer.