Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
Oncogene. 2022 Apr;41(16):2326-2339. doi: 10.1038/s41388-022-02256-3. Epub 2022 Mar 7.
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 a de novo addiction to oncogenic 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 membrane via Rab11-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.
致癌信号赋予肿瘤进展优势；因此，其药理学阻断是癌症化疗的最佳策略。然而，药物耐药性和肿瘤的异质性依赖性阻碍了它们的治疗潜力，这表明需要一种基于规避耐药性的新的普遍模式。在这里，我们提出了一种新的致癌信号成瘾（Dead-On）概念，即通过靶向分子的特异性阻断，迫使癌细胞产生对致癌信号的依赖性。在宫颈鳞状细胞癌细胞中，Aurora A/B 双重阻断会迅速引发对 EGFR-Erk 信号的成瘾，其药理学/遗传学抑制在体外、体内和患者来源的类器官模型中协同增强了抗癌活性。信号激活不依赖于 EGFR 遗传状态，它是通过 Rab11 介导的内吞循环机制在质膜上受体积累触发的。这些发现支持了我们的新的 Dead-On 概念，这可能导致药物发现，并扩大批准的靶向药物的适应性。
