Ferrarotto Renata, Mitani Yoshitsugu, Diao Lixia, Guijarro Irene, Wang Jing, Zweidler-McKay Patrick, Bell Diana, William William N, Glisson Bonnie S, Wick Michael J, Kapoun Ann M, Patnaik Amita, Eckhardt Gail, Munster Pamela, Faoro Leonardo, Dupont Jakob, Lee J Jack, Futreal Andrew, El-Naggar Adel K, Heymach John V
Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
J Clin Oncol. 2017 Jan 20;35(3):352-360. doi: 10.1200/JCO.2016.67.5264. Epub 2016 Nov 21.
Purpose 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. Methods 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. Results 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. Conclusion 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.
腺样囊性癌（ACC）是一组化疗难治性肿瘤，具有异质性，其中一部分表现出侵袭性表型。我们研究了这种表型的分子基础，并评估了Notch1通路作为潜在治疗靶点的可能性。方法：对102例有病理和临床数据的ACC进行基因分型。通过免疫组织化学检测Notch1细胞内结构域来评估Notch1激活情况。采用荧光素酶报告基因检测法在体外确认Notch1靶基因表达。在ACC患者来源的异种移植模型以及一名参加I期研究的ACC患者中测试Notch1抑制剂brontictuzumab。结果：NOTCH1突变主要发生在负调控区和富含脯氨酸-谷氨酸-丝氨酸-苏氨酸的结构域（15例患者中有14例），这与T细胞急性淋巴细胞白血病中出现的两个相同热点区域一致，并导致体外通路激活。基于Notch1细胞内结构域染色，NOTCH1突变型肿瘤显示出比野生型肿瘤显著更高水平的Notch1通路激活（P = 0.004）。NOTCH1突变定义了一个独特的侵袭性ACC亚组，与NOTCH1野生型肿瘤相比，其实体亚型的可能性显著更高（P < 0.001），诊断时处于晚期疾病的比例更高（P = 0.02），肝转移和骨转移率更高（P≤0.02），无复发生存期更短（中位数，13对~34个月；P = 0.01），总生存期更短（中位数30对122个月；P = 0.001）。仅在携带NOTCH1激活突变的ACC患者来源的异种移植模型中观察到brontictuzumab对肿瘤生长有显著抑制作用。此外，一名NOTCH1突变型ACC的指数患者对brontictuzumab有部分反应。结论：NOTCH1突变定义了一种独特的疾病表型，其特征为实体组织学、肝转移和骨转移预后不良以及对Notch1抑制剂可能有反应。针对基因型定义的ACC亚组中Notch1的临床研究是必要的。
