Objective Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited. Design To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets. Results By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer. Conclusions BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway (NCT02884453). Trial registration number NCT02884453; Pre-results

中文翻译：

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绘制遗传脆弱性图谱揭示 BTK 是食管癌的新治疗靶点


目的 食管癌是全球第七大癌症相关死亡原因。疾病复发频繁，治疗选择有限。设计为了确定针对食管癌患者的新的生物标志物定义的治疗方法，我们将 17 种食管肿瘤来源的细胞系的基因组图谱与小分子抑制剂分析的药物敏感性数据进行了整合，确定了与癌症驱动基因改变相关的药物敏感性效应。我们还询问了最近描述的这些肿瘤细胞系的 RNA 干扰筛选数据，以确定可用作治疗靶点的候选遗传依赖性或脆弱性。结果通过将食管肿瘤细胞系的基因组特征与 siRNA 和药物筛选数据相结合，我们确定了食管癌的一系列候选靶标，包括 MYC 扩增的食管肿瘤细胞系中对激酶 BTK 抑制的敏感性。我们发现临床 BTK/ERBB2 激酶抑制剂依鲁替尼可以引发这种遗传依赖性。在 MYC 和 ERBB2 扩增的肿瘤细胞中，依鲁替尼下调 ERK 介导的信号转导、cMYC Ser-62 磷酸化和 MYC 蛋白水平，并引发 G1 细胞周期停滞和细胞凋亡，表明该药物可用于治疗生物标志物选择的群体食道癌患者。结论 BTK 代表了食管癌的一个新的候选治疗靶点，可以作为依鲁替尼的靶向治疗靶点。在这项工作的基础上，目前正在进行一项概念验证 II 期临床试验，评估依鲁替尼对 MYC 和/或 ERBB2 扩增的晚期食管癌患者的疗效 (NCT02884453)。试用注册号NCT02884453；预结果