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

Farhad Ghasemi,John W Barrett,Kara M Ruicci,Joe S Mymryk,Frederick Vizeacoumar,Anthony C Nichols,Alessandro Datti,Paul C Boutros,John Yoo,Laurie A Ailles,Danielle Macneil,David A Palma,Morgan Black,Ren X Sun,Kevin Fung,Eric Winquist,Nicole Pinto

doi:10.18632/oncotarget.25436

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.

Highlights

There has been an epidemic rise in oropharyngeal cancer worldwide due to increasing rates of oral infection with human papillomavirus (HPV) [1, 2]
The distinct tumor characteristics of human papillomavirus (HPV)-positive vs. HPV-negative disease necessitate development of treatment strategies tailored to tumor HPV-status
Multiple studies and clinical trials have identified a superior response to chemotherapy, and better survival outcomes in HPV-positive Head and neck squamous cell carcinoma (HNSCC) compared to the HPV-negative tumors [3, 11,12,13,14]

Summary

Introduction

There has been an epidemic rise in oropharyngeal cancer worldwide due to increasing rates of oral infection with human papillomavirus (HPV) [1, 2]. HPV-positive tumors are distinct from a molecular perspective, with characteristic genetic, epigenetic and protein profiles [4]. Given these profound differences between HPV-positive and HPV-negative disease at the clinical and molecular level, it is logical that the development of any therapy is tailored for the tumor HPV-status. Cell lines are imperfect models of cancer [5, 6], HNSCC cell lines appear to have a similar genomic landscape to primary tumors [7, 8]. Genomic markers of drug sensitivity in cell lines appear to generally correlate well with validated biomarkers in patient tumors [7, 9]. As cell lines can be and cheaply screened with large collections of drugs, they are invaluable tools to identify new agents with potent activity against tumor cells

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Conclusion