Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung cancer.
Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung cancer.
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DOI：
10.1186/s12943-015-0392-3
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发表时间：
2015-06-04
期刊：
影响因子：
37.3
通讯作者：
Lee HY
中科院分区：
文献类型：
--
作者：
Min HY;Yun HJ;Lee JS;Lee HJ;Cho J;Jang HJ;Park SH;Liu D;Oh SH;Lee JJ;Wistuba II;Lee HY
对胰岛素样生长因子受体(IGF-1R)途径的治疗干预有望提供临床益处；然而，IGF-1R酪氨酸激酶抑制剂(TKI)显示出有限的抗肿瘤效果，并且对这些药物传递耐药的机制仍然不清楚。通过可公开获得的数据集的分析以及免疫组织化学、Western blotting、RT-PCR和体外激酶分析来评估IGF-1R和Src的表达和激活。采用四甲基偶氮唑盐比色法、集落形成实验、流式细胞仪分析和异种移植瘤模型分析IGF-1R TKIs单独或与Src抑制剂联合应用的疗效。在多个人非小细胞肺癌细胞系和组织芯片(n = 353)中观察到胰岛素样生长因子-1R和sRc的共激活。IGF-1R和Src蛋白在各自的自磷酸化位点上相互磷酸化。在高PSRC表达的NSCLC细胞中，linsitinib治疗最初使IGF-1R途径失活，但导致下游效应器依赖于Src重新激活。在低PSRC表达的NSCLC细胞中，linsitinib处理降低了IGF-1R和Src蛋白的周转，最终放大了IGF-1R和Src的相互共激活。联合靶向IGF-1R和Src可显著抑制PSRC高表达和低表达的NSCLC细胞的增殖和肿瘤生长，以及体内患者来源组织的生长。在非小细胞肺癌中，Src和IGF-1R之间存在相互激活。SRC通过作为多个膜受体之间串扰的关键下游调节器而导致IGF-1R TKI抵抗。靶向Src是克服对IGF-1R TKIs耐药性的临床适用策略。本文的在线版本(doi：10.1186/s12943-0150392-3)包含补充材料，授权用户可以使用。
Therapeutic interventions in the insulin-like growth factor receptor (IGF-1R) pathway were expected to provide clinical benefits; however, IGF-1R tyrosine kinase inhibitors (TKIs) have shown limited antitumor efficacy, and the mechanisms conveying resistance to these agents remain elusive. The expression and activation of the IGF-1R and Src were assessed via the analysis of a publicly available dataset, as well as immunohistochemistry, Western blotting, RT-PCR, and in vitro kinase assays. The efficacy of IGF-1R TKIs alone or in combination with Src inhibitors was analyzed using MTT assays, colony formation assays, flow cytometric analysis, and xenograft tumor models. The co-activation of IGF-1R and Src was observed in multiple human NSCLC cell lines as well as in a tissue microarray (n = 353). The IGF-1R and Src proteins mutually phosphorylate on their autophosphorylation sites. In high-pSrc-expressing NSCLC cells, linsitinib treatment initially inactivated the IGF-1R pathway but led a Src-dependent reactivation of downstream effectors. In low-pSrc-expressing NSCLC cells, linsitinib treatment decreased the turnover of the IGF-1R and Src proteins, ultimately amplifying the reciprocal co-activation of IGF-1R and Src. Co-targeting IGF-1R and Src significantly suppressed the proliferation and tumor growth of both high-pSrc-expressing and low-pSrc-expressing NSCLC cells in vitro and in vivo and the growth of patient-derived tissues in vivo. Reciprocal activation between Src and IGF-1R occurs in NSCLC. Src causes IGF-1R TKI resistance by acting as a key downstream modulator of the cross-talk between multiple membrane receptors. Targeting Src is a clinically applicable strategy to overcome resistance to IGF-1R TKIs. The online version of this article (doi:10.1186/s12943-015-0392-3) contains supplementary material, which is available to authorized users.
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表皮生长因子受体和K-RAS突变以及肺癌对胰岛素样生长因子1受体酪氨酸激酶抑制剂的耐药性。
影响因子：
6.2
作者：
Kim WY;Prudkin L;Feng L;Kim ES;Hennessy B;Lee JS;Lee JJ;Glisson B;Lippman SM;Wistuba II;Hong WK;Lee HY
通讯作者：
Lee HY
影响因子：
45.3
作者：
Maki, Robert G.
通讯作者：
Maki, Robert G.
DOI：
10.1073/pnas.0502860102
发表时间：
2005-05-24
影响因子：
11.1
作者：
Kwak, EL;Sordella, R;Haber, DA
通讯作者：
Haber, DA
癌症中胰岛素样生长因子和附带途径的双重靶向：对抗耐药性。
影响因子：
5.2
作者：
Ludwig JA;Lamhamedi-Cherradi SE;Lee HY;Naing A;Benjamin R
通讯作者：
Benjamin R
影响因子：
15.8
作者：
Greulich H;Chen TH;Feng W;Jänne PA;Alvarez JV;Zappaterra M;Bulmer SE;Frank DA;Hahn WC;Sellers WR;Meyerson M
通讯作者：
Meyerson M