Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2022 Dec 2;82(23):4444-4456. doi: 10.1158/0008-5472.CAN-22-1175.
Tumor suppressor mutations in head and neck squamous cell carcinoma (HNSCC) dominate the genomic landscape, hindering the development of effective targeted therapies. Truncating and missense mutations in NOTCH1 are frequent in HNSCC, and inhibition of PI3K can selectively target NOTCH1 mutant (NOTCH1MUT) HNSCC cells. In this study, we identify several proteins that are differentially regulated in HNSCC cells after PI3K inhibition based on NOTCH1MUT status. Expression of Aurora kinase B (Aurora B), AKT, and PDK1 following PI3K inhibition was significantly lower in NOTCH1MUT cell lines than in wild-type NOTCH1 (NOTCH1WT) cells or NOTCH1MUT cells with acquired resistance to PI3K inhibition. Combined inhibition of PI3K and Aurora B was synergistic, enhancing apoptosis in vitro and leading to durable tumor regression in vivo. Overexpression of Aurora B in NOTCH1MUT HNSCC cells led to resistance to PI3K inhibition, while Aurora B knockdown increased sensitivity of NOTCH1WT cells. In addition, overexpression of Aurora B in NOTCH1MUT HNSCC cells increased total protein levels of AKT and PDK1. AKT depletion in NOTCH1WT cells and overexpression in NOTCH1MUT cells similarly altered sensitivity to PI3K inhibition, and manipulation of AKT levels affected PDK1 but not Aurora B levels. These data define a novel pathway in which Aurora B upregulates AKT that subsequently increases PDK1 selectively in NOTCH1MUT cells to mediate HNSCC survival in response to PI3K inhibition. These findings may lead to an effective therapeutic approach for HNSCC with NOTCH1MUT while sparing normal cells.
Aurora B signaling facilitates resistance to PI3K inhibition in head and neck squamous cell carcinoma, suggesting that combined inhibition of PI3K and Aurora kinase is a rational therapeutic strategy to overcome resistance.
头颈部鳞状细胞癌（HNSCC）中的肿瘤抑制基因突变主导了基因组景观，阻碍了有效的靶向治疗的发展。NOTCH1 的截断和错义突变在 HNSCC 中很常见，而抑制 PI3K 可以选择性地靶向 NOTCH1 突变（NOTCH1MUT）HNSCC 细胞。在这项研究中，我们根据 NOTCH1MUT 状态，鉴定了几种在 PI3K 抑制后 HNSCC 细胞中差异调节的蛋白质。PI3K 抑制后，Aurora 激酶 B（Aurora B）、AKT 和 PDK1 的表达在 NOTCH1MUT 细胞系中明显低于野生型 NOTCH1（NOTCH1WT）细胞或对 PI3K 抑制获得耐药性的 NOTCH1MUT 细胞。PI3K 和 Aurora B 的联合抑制具有协同作用，增强了体外细胞凋亡，并导致体内持久的肿瘤消退。在 NOTCH1MUT HNSCC 细胞中过表达 Aurora B 导致对 PI3K 抑制的耐药性，而 Aurora B 敲低增加了 NOTCH1WT 细胞的敏感性。此外，在 NOTCH1MUT HNSCC 细胞中过表达 Aurora B 增加了 AKT 和 PDK1 的总蛋白水平。在 NOTCH1WT 细胞中耗尽 AKT 和在 NOTCH1MUT 细胞中过表达 AKT 同样改变了对 PI3K 抑制的敏感性，并且 AKT 水平的操纵影响 PDK1 但不影响 Aurora B 水平。这些数据定义了一种新途径，其中 Aurora B 上调 AKT，随后在 NOTCH1MUT 细胞中选择性地增加 PDK1，以介导 PI3K 抑制下的 HNSCC 存活。这些发现可能为 NOTCH1MUT 的 HNSCC 带来有效的治疗方法，同时避免正常细胞。
Aurora B 信号促进了头颈部鳞状细胞癌对 PI3K 抑制的耐药性，表明 PI3K 和 Aurora 激酶的联合抑制是克服耐药性的合理治疗策略。
