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
Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands.
RNA Interference Functional Oncogenomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
Mol Cancer Ther. 2017 Mar;16(3):540-550. doi: 10.1158/1535-7163.MCT-16-0457. Epub 2016 Dec 15.
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. .
晚期头颈部鳞状细胞癌（HNSCC）患者通常采用含顺铂的放化疗方案进行治疗。尽管顺铂是一种有效的放射增敏剂，但它会导致严重的毒性，而且并非所有患者都能从联合治疗中获益。预期对顺铂无反应的HNSCC患者可能更适合接受手术及术后放疗或西妥昔单抗联合放疗，但目前尚无用于个体化放化疗的生物标志物。我们进行了一项无偏差全基因组功能基因筛选，以鉴定影响HNSCC细胞对顺铂反应的基因。通过小干扰RNA（siRNA）介导的基因敲低，我们确定范可尼贫血/BRCA通路是HNSCC细胞中顺铂反应占主导地位的通路。我们还确定了该基因在DNA交联修复过程中的参与情况。此外，基于这些基因的表达谱可预测接受放疗和放化疗的头颈癌患者的预后。这种全基因组功能分析确定了在HNSCC对顺铂反应中起重要作用的基因，并可能指导进一步的生物标志物验证。顺铂成像以及指示肿瘤中范可尼贫血/BRCA通路活性的生物标志物是主要候选对象。
