Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany.
University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Cancer Discov. 2018 Sep;8(9):1087-1095. doi: 10.1158/2159-8290.CD-18-0036. Epub 2018 May 25.
We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with wild-type () tumors (4 of 17). These alterations included recurrent rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with -rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC. Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as fusions as disease-driving events in tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. .
我们使用全基因组和转录组测序技术，鉴定了年轻的胰腺导管腺癌（PDAC）患者中有临床意义的基因组改变。对参与精准肿瘤学计划的 17 名 PDAC 患者进行的分子特征分析显示，所有野生型（）肿瘤患者（17 名患者中的 4 名）均存在可通过小分子酪氨酸激酶抑制剂抑制的基因融合。这些改变包括通过异常 ERBB 受体介导的信号转导预测驱动 PDAC 发展的反复 重排，并且在 2 名 -重排肿瘤患者中，药物 ERBB 抑制导致肝转移的临床改善和缓解，这些患者对标准治疗已耐药。我们的研究结果表明，对 肿瘤进行致癌融合基因的系统筛查将极大地改善相当一部分 PDAC 患者的治疗前景。晚期 PDAC 是一种恶性肿瘤，治疗选择很少，缺乏基于分子机制的治疗方法。我们的研究揭示了 融合等反复发生的基因重排是 肿瘤的驱动事件，从而为该实体的致癌信号和新的治疗选择提供了新的见解。
