YES1，小细胞肺癌可药化致癌靶点

5 September 2022

YES1 is a druggable oncogenic target in Small Cell Lung Cancer

 (J Thorac Oncol, IF: 20.121)

Redin E, Garrido-Martin EM, Valencia K, et al. YES1 is a druggable oncogenic target in Small Cell Lung Cancer. J Thorac Oncol 2022. DOI: 10.1016/j.jtho.2022.08.002.

Corresponding author: Luis Montuenga，CIMA of the University of Navarra、，Avenida Pío XII, 55, 31008, Pamplona, Spain，e-mail: lmontuenga@unav.es

Rationale 原理

Small cell lung cancer (SCLC) is an extremely aggressive subtype of lung cancer without approved targeted therapies. Here we identified YES1 as a novel targetable oncogene driving SCLC maintenance and metastasis.

小细胞肺癌(SCLC)是一种没有被批准靶向治疗的极具侵袭性的肺癌亚型。在本研究中，我们发现YES1是一种驱动SCLC维持和转移的新型靶向癌基因。

Objectives 目的

To investigate the role of YES1 in SCLC prognosis and evaluate its inhibition as a new therapeutic strategy. 

探讨YES1在SCLC预后中的作用，并评价其抑制作用作为一种新的治疗策略。

Methods 方法

Association between YES1 levels and prognosis was evaluated in SCLC clinical samples. In vitro functional experiments for proliferation, apoptosis, cell cycle and cytotoxicity were performed. Genetic and pharmacological inhibition of YES1 was evaluated in vivo in cell-/patient-derived xenografts (PDXs) and in metastasis. YES1 levels were evaluated in mouse and patients’ plasma-derived exosomes.

在SCLC临床样本中评估YES1水平与预后之间的关系。体外进行细胞增殖、凋亡、细胞周期和细胞毒性功能性实验。在细胞/患者来源的异种移植(PDXs)和转移中，评估了YES1的遗传和药理抑制作用。在小鼠和患者血浆来源的外泌体中评估YES1的水平。

Measurements and Main Results 测量值和主要结果

Overexpression or gain/amplification of YES1 was identified in 31% and 26% of cases, respectively, across molecular subgroups, and was found as an independent predictor of poor prognosis. Genetic depletion of YES1 dramatically reduced cell proliferation, 3D organoid formation, tumor growth and distant metastasis, leading to extensive apoptosis and tumor regressions. Mechanistically, YES1-inhibited cells showed alterations in the replisome and DNA repair processes, that conferred sensitivity to irradiation. Pharmacological blockade with the novel YES1 inhibitor CH6953755 or Dasatinib induced significant anti-tumor activity in organoid models and cell-/patient-derived xenografts. YES1 protein was detected in plasma xosomes from patients and mouse models, with levels matching those of tumors, suggesting that circulating YES1 could represent a biomarker for patient selection/monitoring.

分别有31%和26%的病例在分子亚组中发现了YES1的过表达或获得/扩增，并被发现作为不良预后的独立预测因子。YES1基因缺失显著降低了细胞增殖、3D类器官形成、肿瘤生长和远处转移，导致广泛的凋亡和肿瘤消退。从机制上讲，YES1抑制的细胞显示了复制体和DNA修复过程的改变，这赋予了对放射的敏感性。新型YES1抑制剂CH6953755或达沙替尼的药物阻断在类器官模型和细胞/患者来源的异种移植中诱导了显著的抗肿瘤活性。在患者和小鼠模型的血浆外泌体中检测到YES1蛋白，其水平与肿瘤相匹配，这表明循环YES1可以作为患者选择/监测的生物标志物。

Conclusions 结论

Our results provide evidence that YES1 is a new druggable oncogenic target and biomarker to advance the clinical management of a subpopulation of SCLC patients.

我们的研究结果证明，YES1是一种新的可药物化的致癌靶点和生物标志物，可促进SCLC患者亚群的临床管理。

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