癌症研究
医学
癌症
黑色素瘤
细胞周期
转移
微泡
生物标志物
内科学
生物
生物化学
基因
小RNA
作者
Esther Redín,Eva M. Garrido-Martín,Karmele Valencia,Miriam Redrado,José Luis Solórzano,Rafael Carías,Álvaro Teijeira,Francisco J. Expósito,Diego Serrano,Irene Ferrer,Angel Nunez-Buiza,Irati Garmendia,Juana M. García-Pedrero,Alfonso Gúrpide,Luís Paz-Ares,Katerina Politi,Luis M. Montuenga,Alfonso Calvo
标识
DOI:10.1016/j.jtho.2022.08.002
摘要
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.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 pharmacologic inhibition of YES1 was evaluated in vivo in cell- and patient-derived xenografts and metastasis. YES1 levels were evaluated in mouse and patient plasma-derived exosomes.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, three-dimensional organoid formation, tumor growth, and distant metastasis, leading to extensive apoptosis and tumor regressions. Mechanistically, YES1-inhibited cells revealed alterations in the replisome and DNA repair processes, that conferred sensitivity to irradiation. Pharmacologic blockade with the novel YES1 inhibitor CH6953755 or dasatinib induced marked antitumor activity in organoid models and cell- and patient-derived xenografts. YES1 protein was detected in plasma exosomes from patients and mouse models, with levels matching those of tumors, suggesting that circulating YES1 could represent a biomarker for patient selection/monitoring.Our results provide evidence that YES1 is a new druggable oncogenic target and biomarker to advance the clinical management of a subpopulation of patients with SCLC.
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