Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Bobby R. Alford Department of Otolaryngology, Baylor College of Medicine, Houston, TX 77030, USA.
Cells. 2020 Dec 12;9(12):2677. doi: 10.3390/cells9122677.
Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1's role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer's genetic background, including acquisition of pseudo-stem cell-like properties. The presence of mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC.
生物标志物驱动的靶向治疗对于头颈部鳞状细胞癌（HNSCC）是缺乏的，HNSCC 很常见且致命。开发此类治疗方法的努力受到以肿瘤抑制功能丧失为主导的基因组景观的阻碍，包括在 HNSCC 中经常发生突变的 。更清楚地了解 HNSCC 中的 NOTCH1 信号对于临床靶向该途径至关重要。对头颈部鳞状细胞癌中 突变的结构特征进行分析表明，大多数突变被预测会导致功能丧失，这与 NOTCH1 在这种癌症中作为肿瘤抑制因子的作用一致。在携带突变或野生型 的 HNSCC 细胞系中对 NOTCH1 信号的实验操作进一步支持了肿瘤抑制功能。此外，NOTCH1 信号的丧失可驱动 HNSCC 肿瘤发生和临床侵袭性。我们最近的数据表明，NOTCH1 控制涉及早期分化的基因，这些基因可能根据癌症的遗传背景产生不同的表型后果，包括获得伪干细胞样特性。存在 突变可能预示着对免疫检查点或磷脂酰肌醇 3-激酶抑制剂治疗的反应。后者正在临床试验中进行测试，如果得到验证，它可能会导致针对 HNSCC 的第一种基于生物标志物的靶向治疗方法的开发。
