Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors.
Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors.
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DOI：
10.1200/jco.2016.67.5264
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发表时间：
2017-01-20
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影响因子：
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通讯作者：
Heymach JV
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作者：
Ferrarotto R;Mitani Y;Diao L;Guijarro I;Wang J;Zweidler-McKay P;Bell D;William WN Jr;Glisson BS;Wick MJ;Kapoun AM;Patnaik A;Eckhardt G;Munster P;Faoro L;Dupont J;Lee JJ;Futreal A;El-Naggar AK;Heymach JV
腺样囊性癌是一组异质性的化疗难治性肿瘤，其亚型表现为侵袭性表型。我们研究了这种表型的分子基础，并评估了Notch1通路作为潜在的治疗靶点。我们对102个有可用的病理和临床数据的AC细胞进行了基因分型。用免疫组织化学方法检测Notch1胞内区的激活情况。荧光素酶报告实验证实Notch1靶基因在体外的表达。Notch1抑制剂bratictuzumab在来自ACC患者和一名参加I期研究的ACC患者的患者来源的异种移植中进行了测试。NOTCH1突变主要发生在负调控区和富含Pro-Glu-Ser-Thr的区域(15例患者中有14例)，这两个热点与T细胞急性淋巴细胞白血病相同，并导致了体外途径的激活。Notch1细胞内域染色显示，NOTCH1突变肿瘤的Notch1通路激活水平显著高于野生型肿瘤(P=0.004)。与NOTCH1野生型肿瘤相比，NOTCH1突变定义了一种独特的侵袭性Acc亚型，与NOTCH1野生型肿瘤相比，其实体亚型(P<；.001)、确诊时的晚期疾病(P=0.02)、肝脏和骨转移率(P≤.02)、无复发生存期(中位数为13个月和34个月；P=0.01)和总生存期(中位数30个月和122个月；P=.001)显著更高。在含有NOTCH1激活突变的ACC患者来源的异种移植模型中，Brontictuzumab对肿瘤生长有显著的抑制作用。此外，NOTCH1突变ACC的指标性患者对Brontictuzumab有部分反应。NOTCH1突变定义了一种独特的疾病表型，其特征是坚实的组织学，肝脏和骨转移，预后不良，以及对Notch1抑制剂的潜在反应性。针对基因型定义的ACC亚组中的Notch1的临床研究是有根据的。
Adenoid cystic carcinomas (ACCs) represent a heterogeneous group of chemotherapy refractory tumors, with a subset demonstrating an aggressive phenotype. We investigated the molecular underpinnings of this phenotype and assessed the Notch1 pathway as a potential therapeutic target. We genotyped 102 ACCs that had available pathologic and clinical data. Notch1 activation was assessed by immunohistochemistry for Notch1 intracellular domain. Luciferase reporter assays were used to confirm Notch1 target gene expression in vitro. The Notch1 inhibitor brontictuzumab was tested in patient-derived xenografts from patients with ACC and in a patient with ACC who was enrolled in a phase I study. NOTCH1 mutations occurred predominantly (14 of 15 patients) in the negative regulatory region and Pro-Glu-Ser-Thr–rich domains, the same two hotspots seen in T-cell acute lymphoblastic leukemias, and led to pathway activation in vitro. NOTCH1-mutant tumors demonstrated significantly higher levels of Notch1 pathway activation than wild-type tumors on the basis of Notch1 intracellular domain staining (P = .004). NOTCH1 mutations define a distinct aggressive ACC subgroup with a significantly higher likelihood of solid subtype (P < .001), advanced-stage disease at diagnosis (P = .02), higher rate of liver and bone metastasis (P ≤ .02), shorter relapse-free survival (median, 13 v 34 months; P = .01), and shorter overall survival (median 30 v 122 months; P = .001) when compared with NOTCH1 wild-type tumors. Significant tumor growth inhibition with brontictuzumab was observed exclusively in the ACC patient-derived xenograft model that harbored a NOTCH1 activating mutation. Furthermore, an index patient with NOTCH1-mutant ACC had a partial response to brontictuzumab. NOTCH1 mutations define a distinct disease phenotype characterized by solid histology, liver and bone metastasis, poor prognosis, and potential responsiveness to Notch1 inhibitors. Clinical studies targeting Notch1 in a genotype-defined ACC subgroup are warranted.