Exploiting high-throughput cell line drug screening studies to identify candidate therapeutic agents in head and neck cancer

BMC Clinical Pharmacology

John W Barrett¹  Paul C Boutros³  Benjamin Haibe-Kains²  Andrew Fernandes⁴  Nicole Pinto¹  John Yoo¹  Morgan Black¹  Anthony C Nichols¹ 

[1] Department of Otolaryngology Head & Neck Surgery, Western University, London, Ontario, Canada;Bioinformatics and Computational Genomics Laboratory, Institut de recherches cliniques de Montréal, Université de Montréal, Montreal, Quebec, Canada;Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada;Departments of Biochemistry and Applied Mathematics, Western University, London, Ontario, Canada

关键词: Mutations;    HNSCC;    Genomics;    Cell lines;    High throughput drug screening;   

Others  :  1084565
DOI  :  10.1186/2050-6511-15-66

 received in 2014-04-29, accepted in 2014-11-10,  发布年份 2014

【 摘 要 】

Background

There is an urgent need for better therapeutics in head and neck squamous cell cancer (HNSCC) to improve survival and decrease treatment morbidity. Recent advances in high-throughput drug screening techniques and next-generation sequencing have identified new therapeutic targets in other cancer types, but an HNSCC-specific study has not yet been carried out. We have exploited data from two large-scale cell line projects to clearly describe the mutational and copy number status of HNSCC cell lines and identify candidate drugs with elevated efficacy in HNSCC.

Methods

The genetic landscape of 42 HNSCC cell lines including mutational and copy number data from studies by Garnett et al., and Barretina et al., were analyzed. Data from Garnett et al. was interrogated for relationships between HNSCC cells versus the entire cell line pool using one- and two-way analyses of variance (ANOVAs). As only seven HNSCC cell lines were tested with drugs by Barretina et al., a similar analysis was not carried out.

Results

Recurrent mutations in human papillomavirus (HPV)-negative patient tumors were confirmed in HNSCC cell lines, however additional, recurrent, cell line-specific mutations were identified. Four drugs, Bosutinib, Docetaxel, BIBW2992, and Gefitinib, were found via multiple-test corrected ANOVA to have lower IC₅₀ values, suggesting higher drug sensitivity, in HNSCC lines versus non-HNSCC lines. Furthermore, the PI3K inhibitor AZD6482 demonstrated significantly higher activity (as measured by the IC₅₀) in HNSCC cell lines harbouring PIK3CA mutations versus those that did not.

Conclusion

HNSCC-specific reanalysis of large-scale drug screening studies has identified candidate drugs that may be of therapeutic benefit and provided insights into strategies to target PIK3CA mutant tumors. PIK3CA mutations may represent a predictive biomarker for response to PI3K inhibitors. A large-scale study focused on HNSCC cell lines and including HPV-positive lines is necessary and has the potential to accelerate the development of improved therapeutics for patients suffering with head and neck cancer. This strategy can potentially be used as a template for drug discovery in any cancer type.

【 授权许可】

   
2014 Nichols et al.; licensee BioMed Central Ltd.

【 图 表 】

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