Abstract
BackgroundThere 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.MethodsThe 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.ResultsRecurrent 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.ConclusionHNSCC-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.Electronic supplementary materialThe online version of this article (doi:10.1186/2050-6511-15-66) contains supplementary material, which is available to authorized users.
Highlights
There is an urgent need for better therapeutics in head and neck squamous cell cancer (HNSCC) to improve survival and decrease treatment morbidity
A search of the literature, as well as clinical trials that are currently underway in HNSCC, revealed a variety of agents being investigated that target various cellular molecules
The genetic landscape of HNSCC cell lines is similar to human papillomavirus (HPV)-negative tumors The mutational landscape of the 42 HNSCC cell lines, all of which were HPV-negative [7], demonstrated similarities with primary tumor samples from HPV-negative patients; including frequent mutations in tumor suppressor genes TP53 (74% of cell-lines [9]; 62% of tumors [10]) and CDKN2A, and less frequent ones in PTEN, SMAD4, NOTCH1 and NOTCH2 (Figures 1 and 2)
Summary
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. Despite advances in multi-modal treatment of head and neck squamous cell carcinoma (HNSCC), mortality rates for advance disease remain high [1]. Targeted therapy has become an important method in personalizing treatment for cancer patients based on the genetic mutations present in their tumor(s). Such therapies enable the use of drugs to target molecules within the tumor that are responsible for the malignancy. New strategies are needed to identify active molecules, and to define the target population that is most likely to benefit from therapy
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