Inhibiting Epidermal Growth Factor Receptor Dimerization and Signaling Through Targeted Delivery of a Juxtamembrane Domain Peptide Mimic.
Inhibiting Epidermal Growth Factor Receptor Dimerization and Signaling Through Targeted Delivery of a Juxtamembrane Domain Peptide Mimic.
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DOI：
10.1021/acschembio.8b00555
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发表时间：
2018-09-21
影响因子：
4
通讯作者：
Thévenin D
中科院分区：
文献类型：
--
作者：
Gerhart J;Thévenin AF;Bloch E;King KE;Thévenin D
表皮生长因子受体（EGFR）的过表达和失调与多种人类癌症有关，因此是开发治疗剂的焦点。目前旨在抑制EGFR活性的策略包括单克隆抗体和酪氨酸激酶抑制剂。然而，激活突变严重限制了这些疗法的功效。因此，越来越需要抑制EGFR的新方法。一种有希望的方法涉及阻断EGFR的胞质跨膜（JM）结构域的缔合，其已被证明对于受体二聚化和激酶功能是必需的。在这里，我们的目标是通过利用pH（低）插入肽（pHLIP）来提高EGFR JM肽模拟物的选择性和有效性，pHLIP是一种独特的分子，可以仅基于其细胞外酸性选择性靶向癌细胞。这种递送策略潜在地允许比当前方法更有选择性地靶向肿瘤，并且允许将肽模拟物锚定到质膜的细胞质小叶，增加其局部浓度，从而增加功效。我们表明，缀合的构建体能够抑制EGFR磷酸化和下游信号传导，并诱导宫颈癌细胞中的浓度和pH依赖性毒性。我们设想，这种方法可以扩展到其他单跨膜受体的活动介导的JM域的调制。
Overexpression and deregulation of the epidermal growth factor receptor (EGFR) are implicated in multiple human cancers and therefore are a focus for the development of therapeutics. Current strategies aimed at inhibiting EGFR activity include monoclonal antibodies and tyrosine kinase inhibitors. However, activating mutations severely limit the efficacy of these therapeutics. There is thus a growing need for novel methods to inhibit EGFR. One promising approach involves blocking the association of the cytoplasmic juxtamembrane (JM) domain of EGFR, which has been shown to be essential for receptor dimerization and kinase function. Here, we aim to improve the selectivity and efficacy of an EGFR JM peptide mimic by utilizing the pH(low) insertion peptide (pHLIP), a unique molecule that can selectively target cancer cells solely based on their extracellular acidity. This delivery strategy potentially allows for more selective targeting to tumors than current methods and for anchoring the peptide mimic to the cytoplasmic leaflet of the plasma membrane, increasing its local concentration and thus efficacy. We show that the conjugated construct is capable of inhibiting EGFR phosphorylation and downstream signaling and of inducing concentration- and pH-dependent toxicity in cervical cancer cells. We envision that this approach could be expanded to the modulation of other single-span membrane receptors whose activity is mediated by JM domains.
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DOI：
10.1016/b978-0-12-397927-8.00004-x
发表时间：
2012
期刊：
Advances in pharmacology (San Diego, Calif.)
影响因子：
--
作者：
Bailey, Kate M;Wojtkowiak, Jonathan W;Hashim, Arig Ibrahim;Gillies, Robert J
通讯作者：
Gillies, Robert J
DOI：
10.1073/pnas.1608247113
发表时间：
2016-07-19
影响因子：
11.1
作者：
Anderson, Michael;Moshnikova, Anna;Andreev, Oleg A.
通讯作者：
Andreev, Oleg A.
影响因子：
14.8
作者：
Luedtke, Nathan W.;Dexter, Rachel J.;Schepartz, Alanna
通讯作者：
Schepartz, Alanna
影响因子：
4.9
作者：
Burns, Kelly E.;Hensley, Harvey;Thevenin, Damien
通讯作者：
Thevenin, Damien
影响因子：
14.8
作者：
Liang, Chun-Chi;Park, Ann Y.;Guan, Jun-Lin
通讯作者：
Guan, Jun-Lin