Illuminating biological pathways for drug targeting in head and neck squamous cell carcinoma

Autoři: Gabrielle Choonoo aff001;  Aurora S. Blucher aff001;  Samuel Higgins aff002;  Mitzi Boardman aff002;  Sophia Jeng aff001;  Christina Zheng aff001;  James Jacobs aff001;  Ashley Anderson aff006;  Steven Chamberlin aff002;  Nathaniel Evans aff002;  Myles Vigoda aff003;  Benjamin Cordier aff002;  Jeffrey W. Tyner aff001;  Molly Kulesz-Martin aff003;  Shannon K. McWeeney aff001;  Ted Laderas aff001
Působiště autorů: Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America aff001;  Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America aff002;  Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America aff003;  Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America aff004;  Pediatric Hematology and Oncology, OHSU Doernbecher Children’s Hospital, Portland, Oregon, United States of America aff005;  Department of Dermatology, Oregon Health & Science University, Portland, Oregon, United States of America aff006;  Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon, United States of America aff007
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223639


Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either “light” or “dark” to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35–38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development.

Klíčová slova:

Cancer treatment – Drug discovery – Drug research and development – Head and neck squamous cell carcinoma – Human papillomavirus – Mutation – Radiation therapy – Somatic mutation


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