Abstract 5136: Identification of sensitizers of platinum-based therapy in head and neck cancer using a functional genomics approach

Abstract

Abstract Objective The prevalence and mortality for head and neck cancer (HNC) has not improved significantly in the last several decades. It is the sixth most common cancer with an estimated 600,000 new cases diagnosed worldwide every year and has ∼50% 5-year survival rate. Of these, 47000 new cases are diagnosed in the US annually. The most common risk factors for HNC are tobacco and alcohol use but a growing subset is also attributed to human papillomavirus (HPV) infection. Late stage HNCs are treated with a combination of surgery, radiation, and chemotherapy (often platinum-based), but the cancers treated with platinum-based chemotherapy often develop drug resistance. Identification of target genes using high-throughput RNAi (HT-RNAi) gene-silencing technology has become an increasingly popular method in the field of cancer research. The objective of our study is to use this functional genomics based approach to identify genes that, when silenced, increase the sensitivity of the platinum drugs. This would possibly help us in identifying potentiators of platinum-based drugs to more effectively treat HNC patients. Methods We performed drug dose response (DDR) experiments on nine HNC cell lines; including two are HPV-positive lines, to identify cisplatin-resistant and -sensitive cancer cell lines. To identify sensitizers of cisplatin response, we used a siRNA library targeting 572 kinases. Each kinase is represented by two different siRNA sequences in the library. Based on the data mined from published literature on head and neck cancer as well as genes thought to confer a functional relationship between HPV infection and HNC, a more focused siRNA library was also designed and included in the screening. Cell lines were reverse transfected with the siRNAs in a 384 well format, dosed with cisplatin after 24 hours and the plates were read 72 hours later. Results We calculated the inhibitory concentrations using DDR experiments for all the nine HNC cell lines and identified cisplatin-resistant (UMSCC47 and SCC9) and -sensitive (Cal27, UMSCC14C, and SCC090) HNC cell lines. HT-RNAi experiments have been performed on the cisplatin-resistant cell lines, one of which is HPV-positive. After data analysis, confirmation of silencing and validation of drug modulation will be done on a subset of candidate genes. Conclusions HNC patients with surgically non-resectable tumors could have improved treatment with chemotherapeutic drugs; however, acquired drug resistance often inhibits a successful treatment. Identification of sensitizing targets may provide hope for a better outcome, but may also allow for use of smaller doses of more toxic drugs, such as cisplatin. In addition, this study may also identify alternate genes that can be targeted in the subset of HPV-positive HNC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5136. doi:1538-7445.AM2012-5136