The FA/BRCA Pathway Identified as the Major Predictor of Cisplatin Response in Head and Neck Cancer by Functional Genomics

• Published in: Molecular cancer therapeutics 2017-03, Vol.16 (3), p.540-550
• Main Authors: Martens-de Kemp, Sanne R, Brink, Arjen, van der Meulen, Ida H, de Menezes, Renée X, Te Beest, Dennis E, Leemans, C René, van Beusechem, Victor W, Braakhuis, Boudewijn J M, Brakenhoff, Ruud H
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents - pharmacology; Biomarkers; Breast cancer; Cancer; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - mortality; Cell Cycle - genetics; Cell Line, Tumor; Chemoradiotherapy; Cisplatin; Cisplatin - pharmacology; Crosslinking; Deoxyribonucleic acid; DNA; DNA repair; Drug Resistance, Neoplasm - genetics; Fanconi Anemia Complementation Group Proteins - metabolism; Fanconi syndrome; Female; Functional analysis; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic screening; Genome-Wide Association Study; Genomes; Genomics; Genomics - methods; Head; Head & neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - mortality; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Monoclonal antibodies; Patients; Radiation; RNA, Small Interfering - genetics; Signal Transduction; siRNA; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Surgery; Targeted cancer therapy; Toxicity; Tumors
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0457

Patients with advanced stage head and neck squamous cell carcinoma (HNSCC) are often treated with cisplatin-containing chemoradiation protocols. Although cisplatin is an effective radiation sensitizer, it causes severe toxicity and not all patients benefit from the combination treatment. HNSCCs expectedly not responding to cisplatin may better be treated with surgery and postoperative radiation or cetuximab and radiation, but biomarkers to personalize chemoradiotherapy are not available. We performed an unbiased genome-wide functional genetic screen to identify genes that influence the response to cisplatin in HNSCC cells. By siRNA-mediated knockdown, we identified the Fanconi anemia/BRCA pathway as the predominant pathway for cisplatin response in HNSCC cells. We also identified the involvement of the gene in the process of DNA cross-link repair. Furthermore, expression profiles based on these genes predict the prognosis of radiation- and chemoradiation-treated head and neck cancer patients. This genome-wide functional analysis designated the genes that are important in the response of HNSCC to cisplatin and may guide further biomarker validation. Cisplatin imaging as well as biomarkers that indicate the activity of the Fanconi anemia/BRCA pathway in the tumors are the prime candidates. .