Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling
Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling
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DOI：
10.1038/s41388-022-02256-3
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发表时间：
2022-03
期刊：
影响因子：
8
通讯作者：
Masayuki Komatsu;Kanako Nakamura;T. Takeda;F. Chiwaki;K. Banno;D. Aoki;F. Takeshita;Hiroki Sasaki
中科院分区：
文献类型：
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作者：
Masayuki Komatsu;Kanako Nakamura;T. Takeda;F. Chiwaki;K. Banno;D. Aoki;F. Takeshita;Hiroki Sasaki
致癌信号传递赋予肿瘤进展优势;因此，其药理学阻断是癌症化疗的最佳策略。然而，肿瘤的耐药性和异质性依赖性阻碍了它们的治疗潜力，这表明有必要建立一种基于逃避耐药性的新的普遍存在的方式。在这里，我们提出了adenovodicity致癌信号（死）的概念，其中靶分子的特异性阻断迫使癌细胞发展依赖于致癌信号。在宫颈鳞状细胞癌细胞中，Aurora A/B双重阻断引起对EGFR-Erk信号传导的快速成瘾，其药理学/遗传抑制在体外、体内和患者源性类器官模型中协同增强抗癌活性。该信号激活与EGFR基因状态无关，它是由受体在质膜上的积累触发的Rab 11介导的内吞再循环机制。这些发现支持了我们新的Dead-On概念，这可能会导致药物发现以及扩大批准的靶向药物的适应性。
Oncogenic signalling confers tumour-progression advantages; thus, its pharmacological blockade is the best strategy for cancer chemotherapy. However, drug resistance and heterogeneous dependency of tumour hamper their therapeutic potential, suggesting the necessity for a new ubiquitous modality based on evading drug resistance. Here, we proposed adenovoaddiction tooncogenic signalling (Dead-On) concept, wherein specific blockade of target molecules forces cancer cells to develop dependency on an oncogenic signalling. In cervical squamous cell carcinoma cells, Aurora A/B dual blockade elicited rapid addiction to EGFR–Erk signalling, and its pharmacological/genetic inhibition synergistically enhanced anti-cancer activities in vitro, in vivo, and in a patient-derived organoid model. The signal activation was independent of EGFR genetic status, it was triggered by receptor accumulation on the plasma membraneviaRab11-mediated endocytic recycling machinery. These findings support our novel Dead-On concept which may lead to drug discovery as well as expand the adaptation of approved targeted drugs.