Synergistic therapeutic effect of combined PDGFR and SGK1 inhibition in metastasis-initiating cells of breast cancer
Synergistic therapeutic effect of combined PDGFR and SGK1 inhibition in metastasis-initiating cells of breast cancer
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PDGFR和SGK1联合抑制对乳腺癌转移起始细胞的协同治疗作用
DOI：
10.1038/s41418-019-0485-4
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Xiaoming Xie
中科院分区：
文献类型：
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作者：
Lu Yang;Ning Li;Zhicheng Xue;Ling Rui Liu;Jian Li;Xiaojia Huang;Xiaoming Xie;Yutian Zou;Hailin Tang;Xiaoming Xie
缺乏对引发转移的细胞身份的了解阻碍了抗转移疗法的发展。只有一小部分被称为转移起始细胞（MIC）的肿瘤细胞能够成功播种转移，从而导致复发和治疗耐药。使用转移模型，我们描述了源自肺转移瘤的 MIC 亚群，这些亚群不具有增殖优势，表达高水平的 PDGF 受体和 EMT/干细胞相关基因，并且具有独特的启动转移能力。 PDGF 因子以 PDGFR 依赖性方式特异性增强 MIC 群体的转移潜力。然而，PDGFR 抑制优先抑制肺转移，但不会减少原发肿瘤负荷。因此，我们发现 PDGFR 抑制会阻断 AKT 激活，而 SGK1 与 AKT 过表达共享高相似性激酶结构域和重叠底物，因此在 MIC 中仍保持活性。 SGK1 和 PDGF 信号传导协同作用，促进转移形成，抑制 SGK1 会导致对 PDGFR 抑制剂的脆弱性，从而产生强大的抗肿瘤作用。在体内，SGK1 抑制剂通过减少原发性肿瘤生长和肺转移，使异种移植肿瘤对 PDGFR 靶向疗法敏感。因此，PDGFR 和 SGK1 的双重抑制在体外和体内建立的乳腺癌细胞系中表现出强大的抗肿瘤活性。因此，这种方法不仅提供了对 MIC 转化的深入了解，而且有助于设计改进的晚期乳腺癌治疗策略。
Lack of insight into the identity of the cells that initiate metastasis hampers the development of antimetastatic therapies. Only a tiny fraction of tumor cells termed metastasis-initiating cells (MICs) are able to successfully seed metastases, causing recurrence and therapeutic resistance. Using metastasis models, we describe a subpopulation of MIC derivates from lung metastases that do not have proliferation advantages, express high levels of the PDGF receptors and EMT/stemness-related genes, and are unique in their ability to initiate metastasis. PDGF factors specifically boost the metastatic potential of MIC populations in a PDGFR-dependent manner. However, PDGFR inhibition preferentially suppresses lung metastases, but does not reduce the primary tumor burden. Thus, we found that PDGFR inhibition blocks AKT activation, whereas SGK1, which shares high-similarity kinase domain and overlap substrates with AKT overexpression remains active in MICs. SGK1 and PDGF signaling act in concert to promote metastatic formation, and SGK1 inhibition confers vulnerability to PDGFR inhibitors, also eliciting a powerful antitumor effect. In vivo, SGK1 inhibitors sensitize xenograft tumors to PDGFR-targeted therapies by reducing primary tumor growth and lung metastasis. Consequently, dual inhibition of PDGFR and SGK1 exhibited strong antitumor activities in established breast cancer cell lines in vitro and in vivo. Therefore, this approach not only provides insight into MIC transformation but also aids the design of improved therapeutic strategies for advanced breast cancer.