High-throughput testing in head and neck squamous cell carcinoma identifies agents with preferential activity in human papillomavirus-positive or negative cell lines

摘要

// Farhad Ghasemi 1, * , Morgan Black 1, 2, * , Ren X. Sun 3, 4 , Frederick Vizeacoumar 5 , Nicole Pinto 1, 2 , Kara M. Ruicci 1, 2 , John Yoo 1, 2 , Kevin Fung 1, 2 , Danielle MacNeil 1, 2 , David A. Palma 2 , Eric Winquist 2 , Joe S. Mymryk 1, 2, 6 , Laurie A. Ailles 7 , Alessandro Datti 8, 9 , John W. Barrett 1, 2, ** , Paul C. Boutros 3, 4, 7, ** and Anthony C. Nichols 1, 2, ** 1 Department of Otolaryngology – Head and Neck Surgery, London Health Sciences Centre, London, Ontario, Canada 2 Department of Oncology, London Health Sciences Centre, London, Ontario, Canada 3 Ontario Institute of Cancer Research, MaRS Centre, Toronto, Ontario, Canada 4 Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada 5 Cancer Research Cluster, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 6 Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada 7 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 8 Network Biology Collaborative Centre, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada 9 Department of Agricultural, Food, and Environmental Sciences, University of Perugia, Perugia, Italy * These authors have contributed equally to this paper ** These authors have contributed equally to this paper Correspondence to: Anthony C. Nichols, email: [email protected] Keywords: head and neck cancer; human papillomavirus; high throughput drug testing; cell lines; chemotherapy Abbreviations: HNSCC: Head and Neck Squamous Cell Carcinoma; HPV: Human papillomavirus; IC 50 : half-maximal inhibitory concentration Received: February 08, 2018      Accepted: April 28, 2018      Published: May 25, 2018 ABSTRACT Head and neck squamous cell carcinoma (HNSCC) is a common cancer diagnosis worldwide. Despite advances in treatment, HNSCC has very poor survival outcomes, emphasizing an ongoing need for development of improved therapeutic options. The distinct tumor characteristics of human papillomavirus (HPV)-positive vs . HPV-negative disease necessitate development of treatment strategies tailored to tumor HPV-status. High-throughput robotic screening of 1,433 biologically and pharmacologically relevant compounds at a single dose (4 μM) was carried out against 6 HPV-positive and 20 HPV-negative HNSCC cell lines for preliminary identification of therapeutically relevant compounds. Statistical analysis was further carried out to differentiate compounds with preferential activity against cell lines stratified by the HPV-status. These analyses yielded 57 compounds with higher activity in HPV-negative cell lines, and 34 with higher-activity in HPV-positive ones. Multi-point dose-response curves were generated for six of these compounds (Ryuvidine, MK-1775, SNS-032, Flavopiridol, AZD-7762 and ARP-101), confirming Ryuvidine to have preferential potency against HPV-negative cell lines, and MK-1775 to have preferential potency against HPV-positive cell lines. These data comprise a valuable resource for further investigation of compounds with therapeutic potential in the HNSCC.