A genome - wide siRNA screen identi ies the FA / BRCA pathway as the strongest predictor of cisplatin response in head and neck cancer cells

A genome-wide siRNA screen identiiies the FA/BRCA pathway as the strongest predictor of cisplatin response in head and neck cancer cells. ABSTRACT Objective: Patients with advanced head and neck squamous cell carcinoma (HNSCC) are generally treated with cisplatin-containing chemoradiation protocols. Although cisplatin is a low-priced and often used addition to radiation, it causes severe toxicity and not all patients beneeit from the treatment. Non-responding HNSCC patients may better be treated with surgery and postoperative radiation, but biomarkers of chemoradiation response, that would allow personalized treatment, are not available. Methods: We performed an unbiased genome-wide functional genetic screen in vitro to identify genes that innluence the response to cisplatin in HNSCC cells. Results: We identiiied 269 genes of which siRNA-mediated knockdown seemed to signiiicantly innluenced cisplatin response in HNSCC cells. We retested 149 siRNA pools and were able to connirm that 21 genes are important in the cisplatin response in three HNSCC cell lines. The predominant pathway involved in this response is the Fanconi anemia/BRCA pathway, including the SHFM1 gene. Conclusion: This genome-wide functional analysis identiiied genes that are important in the response of HNSCC to cisplatin and may guide further biomarker validation. Biomarkers that indicate the activity of the Fanconi anemia/BRCA pathway are the irst logical candidates.