Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer
Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer
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DOI：
10.1093/annonc/mdx523
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发表时间：
2017-12-01
影响因子：
50.5
通讯作者：
Laskin, J.
中科院分区：
文献类型：
--
作者：
Jones, M. R.;Lim, H.;Laskin, J.
背景：NRG1融合阳性肺癌已经成为肺癌潜在的可操作事件，但目前临床支持有限，而且没有证据表明这种方法在肺癌以外的癌症中有效。患者和方法：在这里，我们描述了两例标准治疗无效的晚期癌症患者。1例为肺腺癌，2例为胆管细胞癌。对这些病例进行全基因组和转录组测序，并经荧光原位杂交证实。结果：两例肿瘤均为NRG1基因融合阳性。在患者1中，检测到SDC4-NRG1基因融合，以前在肺癌中也描述了类似的基因融合。在患者2中，检测到一种新的ATP1B1-NRG1基因融合。胆管细胞癌不是一种以前描述过的NRG1融合的疾病类型。综合基因组分析用于评估检测到的基因组事件的潜在功能意义，包括基因融合，优先考虑针对HER-家族生长因子受体的治疗策略。这两名患者都接受了PAN HER家族激酶抑制剂afatinib的治疗，两人对治疗都显示出显著和持久的反应。在疾病进展时，对疾病的部位进行测序。缺乏明显的基因组事件来描述疾病的进展表明，广泛的转录或表观遗传机制可能归因于缺乏对afatinib的长期反应。结论：这些观察进一步支持在肺癌和肝细胞癌中使用PAN酪氨酸激酶抑制剂治疗NRG1融合阳性，并更广泛地表明，被发现NRG1融合阳性的癌症可能受益于这种临床方法，无论它们起源于哪里。临床试验信息：不列颠哥伦比亚省的个性化肿瘤基因组学(POG)计划：利用基因组分析更好地了解肿瘤的异质性和进化(NCT02155621)。
Background: NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers beyond lung has been shown.Patients and methods: Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization.Results: Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4-NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1-NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib.Conclusion: These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin.Clinical trial information: Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621).