Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations.
Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations.
复制标题
DOI：
10.1016/j.canlet.2012.01.011
复制
发表时间：
2012-05-28
期刊：
影响因子：
9.7
通讯作者：
Lo, Hui-Wen
中科院分区：
文献类型：
--
作者：
Han, Woody;Lo, Hui-Wen
表皮生长因子受体（EGFR）途径是人类癌症中最失调的分子途径之一。尽管在过去的几十年中，EGFR在肿瘤生长、进展和耐药表型方面的重要性已得到公认，但设计用于规避EGFR的靶向治疗在癌症患者中仅取得了适度的临床成功，携带EGFR激活突变的非小细胞肺癌（NSCLC）患者除外。然而，几乎所有这些NSCLC患者最终都对小分子EGFR激酶抑制剂产生了耐药性。这些令人失望的结果部分是由于EGFR信号网络的高度复杂性和相互作用的性质。最近令人信服的证据进一步表明，EGFR的功能可能取决于其亚细胞位置。在这方面，EGFR经历易位到不同的细胞器中，在那里它发挥与其作为质膜结合受体酪氨酸激酶的最佳已知活性明显不同的功能。EGFR可在配体结合、放射、EGFR靶向治疗和其他刺激下穿梭进入细胞核和胞浆。核EGFR作为转录调节因子、酪氨酸激酶和其他生理过程的介体。线粒体EGFR的作用仍然知之甚少，但它似乎调节细胞凋亡。虽然使用患者肿瘤的研究表明，细胞核EGFR是癌症患者临床预后不良的指标，但线粒体EGFR对肿瘤行为和患者预后的影响仍有待确定。最近，一些证据表明，EGFR的错位可能会调节肿瘤对治疗的反应，而质膜结合的EGFR不依赖于其激酶活性而释放生存信号。鉴于这些最新的进展和发现，我们将在这篇小综述中概述一个新兴的研究路线，该路线揭示了EGFR信号传导的几种新模式，并在功能上表征了这些模式在细胞核，细胞核和其他亚细胞区室中的中心阶段。我们还将讨论这些发现在克服肿瘤耐药性的治疗策略的基本原理设计中的临床意义。
The epidermal growth factor receptor (EGFR) pathway is one of the most dysregulated molecular pathways in human cancers. Despite its well-established importance in tumor growth, progression and drug-resistant phenotype over the past several decades, targeted therapy designed to circumvent EGFR has yielded only modest clinical success in cancer patients, except those with non-small cell lung cancer (NSCLC) carrying EGFR activation mutations. However, almost all of these NSCLC patients eventually developed resistance to small molecule EGFR kinase inhibitors. These disappointing outcomes are, in part, due to the high complexity and the interactive nature of the EGFR signaling network. More recent compelling evidence further indicates that EGFR functionality can be dependent on its subcellular location. In this regard, EGFR undergoes translocation into different organelles where it elicits distinctly different functions than its best known activity as a plasma membrane-bound receptor tyrosine kinase. EGFR can be shuttled into the cell nucleus and mitochondrion upon ligand binding, radiation, EGFR-targeted therapy and other stimuli. Nuclear EGFR behaves as transcriptional regulator, tyrosine kinase, and mediator of other physiological processes. The role of mitochondrial EGFR remains poorly understood but it appears to regulate apoptosis. While studies using patient tumors have shown nuclear EGFR to be an indicator for poor clinical outcomes in cancer patients, the impact of mitochondrial EGFR on tumor behavior and patient prognosis remains to be defined. Most recently, several lines of evidence suggest that mislocated EGFR may regulate tumor response to therapy and that plasma membrane-bound EGFR elicits survival signals independent of its kinase activity. In light of these recent progresses and discoveries, we will outline in this minireview an emerging line of research that uncovers and functionally characterizes several novel modes of EGFR signaling that take center stage in the cell nucleus, mitochondrion and other subcellular compartments. We will also discuss the clinical implications of these findings in the rationale design for therapeutic strategy that overcomes tumor drug resistance.
登录
查看更多内容
影响因子：
56.9
作者：
ANDERSON, D;KOCH, CA;PAWSON, T
通讯作者：
PAWSON, T
影响因子：
50.3
作者：
Baselga, J;Norton, L
通讯作者：
Norton, L
影响因子：
30.8
作者：
Bell, DW;Gore, I;Haber, DA
通讯作者：
Haber, DA
影响因子：
5.3
作者：
Boerner, JL;Demory, ML;Parsons, SJ
通讯作者：
Parsons, SJ
DOI：
10.1073/pnas.91.15.6967
发表时间：
1994-07-19
影响因子：
11.1
作者：
COKER, KJ;STAROS, JV;GUYER, CA
通讯作者：
GUYER, CA