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This article is the authors’ final published version in Cancer, Volume 13, Issue 11, June 2021, Article number 2774.

The published version is available at Copyright © van Harten & Brakenhoff


Head and neck squamous cell carcinomas (HNSCC) develop in the mucosal lining ofthe upper-aerodigestive tract. In carcinogen-induced HNSCC, tumors emerge from premalignantmucosal changes characterized by tumor-associated genetic alterations, also coined as ‘fields’ that areoccasionally visible as leukoplakia or erythroplakia lesions but are mostly invisible. Consequently,HNSCC is generally diagnosedde novoat more advanced stages in about 70% of new diagnosis.Despite intense multimodality treatment protocols, the overall 5-years survival rate is 50–60% forpatients with advanced stage of disease and seems to have reached a plateau. Of notable concern isthe lack of further improvement in prognosis despite advances in treatment. This can be attributedto the late clinical presentation, failure of advanced HNSCC to respond to treatment, the deficit ofeffective targeted therapies to eradicate tumors and precancerous changes, and the lack of suitablemarkers for screening and personalized therapy. The molecular landscape of head and neck cancerhas been elucidated in great detail, but the absence of oncogenic mutations hampers the identificationof druggable targets for therapy to improve outcome of HNSCC. Currently, functional genomicapproaches are being explored to identify potential therapeutic targets. Identification and validationof essential genes for both HNSCC and oral premalignancies, accompanied with biomarkers fortherapy response, are being investigated. Attentive diagnosis and targeted therapy of the precedingoral premalignant (preHNSCC) changes may prevent the development of tumors. As classic oncogeneaddiction through activating mutations is not a realistic concept for treatment of HNSCC, syntheticlethality and collateral lethality need to be exploited, next to immune therapies. In recent studiesit was shown that cell cycle regulation and DNA damage response pathways become significantlyaltered in HNSCC causing replication stress, which is an avenue that deserves further exploitation asan HNSCC vulnerability for treatment. The focus of this review is to summarize the current literatureon the preclinical identification of potential druggable targets for therapy of (pre)HNSCC, emerging from the variety of gene knockdown and knockout strategies, and the testing of targeted inhibitors.We will conclude with a future perspective on targeted therapy of HNSCC and premalignant changes.

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This work is licensed under a Creative Commons Attribution 4.0 License.