Huang Kie Kyon, Jang Kang Won, Kim Sangwoo, Kim Han Sang, Kim Sung-Moo, Kwon Hyeong Ju, Kim Hye Ryun, Yun Hwan Jung, Ahn Myung Ju, Park Keon Uk, Ramnarayanan Kalpana, McPherson John R, Zhang Shenli, Rhee Je-Keun, Vettore André L, Das Kakoli, Ishimoto Takatsugu, Kim Joo Hang, Koh Yoon Woo, Kim Se Hun, Choi Eun Chang, Teh Bin Tean, Rozen Steven G, Kim Tae-Min, Tan Patrick, Cho Byoung Chul
Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore, Singapore.
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
Sci Rep. 2016 Jan 21;6:19552. doi: 10.1038/srep19552.
Dacomitinib, an irreversible pan-HER inhibitor, had shown modest clinical activity in squamous cell carcinoma of head and neck (SCCHN) patients. Therefore, validated predictive biomarkers are required to identify patients most likely to benefit from this therapeutic option. To characterize the genetic landscape of cisplatin-treated SCCHN genomes and identify potential predictive biomarkers for dacomitinib sensitivity, we performed whole exome sequencing on 18 cisplatin-resistant metastatic SCCHN tumors and their matched germline DNA. Platinum-based chemotherapy elevated the mutation rates of SCCHN compared to chemotherapy-naïve SCCHNs. Cisplatin-treated SCCHN genomes uniquely exhibited a novel mutational signature characterized by C:G to A:T transversions at CCR sequence contexts that may have arisen due to error-prone translesional synthesis. Somatic mutations in REV3L, the gene encoding the catalytic subunit of DNA polymerase ζ involved in translesional synthesis, are significantly enriched in a subset of patients who derived extended clinical benefit to dacomitinib (P = 0.04). Functional assays showed that loss-of-function of REV3L dramatically enhanced the sensitivity of SCCHN cells to dacomitinib by the loss of both translesion synthesis and homologous recombination pathways. Our data suggest that the 'platinum' mutational signature and inactivation of REV3L may inform treatment options in patients of recurrent SCCHN.
达克替尼是一种不可逆的泛HER抑制剂，已在头颈部鳞状细胞癌（SCCHN）患者中显示出一定的临床活性。因此，需要经过验证的预测性生物标志物来识别最有可能从这种治疗选择中获益的患者。为了描绘顺铂治疗的SCCHN基因组的遗传图谱，并确定达克替尼敏感性的潜在预测性生物标志物，我们对18例顺铂耐药的转移性SCCHN肿瘤及其匹配的种系DNA进行了全外显子组测序。与未接受过化疗的SCCHN相比，铂类化疗提高了SCCHN的突变率。顺铂治疗的SCCHN基因组独特地表现出一种新的突变特征，其特点是在CCR序列背景下发生C:G到A:T的颠换，这可能是由于易错跨损伤合成所致。REV3L（编码参与跨损伤合成的DNA聚合酶ζ催化亚基的基因）中的体细胞突变在从达克替尼中获得延长临床获益的一部分患者中显著富集（P = 0.04）。功能分析表明，REV3L功能丧失通过跨损伤合成和同源重组途径的丧失，显著增强了SCCHN细胞对达克替尼的敏感性。我们的数据表明，“铂”突变特征和REV3L失活可能为复发性SCCHN患者的治疗选择提供依据。
