An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition.
An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition.
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DOI：
10.1038/ncb2953
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发表时间：
2014-05
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
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作者：
肿瘤细胞具有类似干细胞的特性，具有高度侵袭性，并且经常表现出耐药性。在这里，我们发现整合素 αvβ3 可作为乳腺癌、肺癌和胰腺癌的标志物，具有类似干细胞的特性，对受体酪氨酸激酶抑制剂（如厄洛替尼）具有高度耐药性。这是在体外、在携带患者来源的肿瘤异种移植物的小鼠或在接受厄洛替尼治疗后病情进展的肺癌患者的临床标本中观察到的。从机制上讲，未连接状态下的 αvβ3 将 KRAS 和 RalB 招募到肿瘤细胞质膜，导致 TBK-1/NFκB 激活。事实上，αvβ3 表达和由此产生的 KRAS/RalB/NFκB 通路对于肿瘤发生、锚定独立、自我更新和厄洛替尼耐药都是必要且充分的。硼替佐米对该途径的药理学靶向逆转了肿瘤干性和厄洛替尼耐药性。这些发现不仅将 αvβ3 确定为癌症干性的标记/驱动因素，而且揭示了一种使此类肿瘤对 RTK 抑制敏感的治疗策略。
Tumor cells, with stem-like properties, are highly aggressive and often display drug resistance. Here, we reveal that integrin αvβ3 serves as a marker of breast, lung, and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumor xenografts or in clinical specimens from lung cancer patients that had progressed on erlotinib. Mechanistically, αvβ3, in the unligated state, recruits KRAS and RalB to the tumor cell plasma membrane, leading to the activation of TBK-1/NFκB. In fact, αvβ3 expression and the resulting KRAS/RalB/NFκB pathway were both necessary and sufficient for tumor initiation, anchorage-independence, self-renewal, and erlotinib resistance. Pharmacological targeting of this pathway with Bortezomib reversed both tumor stemness and erlotinib resistance. These findings not only identify αvβ3 as a marker/driver of carcinoma stemness but they reveal a therapeutic strategy to sensitize such tumors to RTK inhibition.
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影响因子：
45.3
作者：
Liu, Suling;Wicha, Max S.
通讯作者：
Wicha, Max S.
影响因子：
11.2
作者：
Knowles LM;Gurski LA;Engel C;Gnarra JR;Maranchie JK;Pilch J
通讯作者：
Pilch J
DOI：
10.4161/cc.8.20.9761
发表时间：
2009-10-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Ginestier C;Wicinski J;Cervera N;Monville F;Finetti P;Bertucci F;Wicha MS;Birnbaum D;Charafe-Jauffret E
通讯作者：
Charafe-Jauffret E
影响因子：
5.3
作者：
Evellin, Sandrine;Galvagni, Federico;Oliviero, Salvatore
通讯作者：
Oliviero, Salvatore
影响因子：
15.9
作者：
Cascone, Tina;Herynk, Matthew H.;Heymach, John V.
通讯作者：
Heymach, John V.