Cigarette smoke induces aberrant EGF receptor activation that mediates lung cancer development and resistance to tyrosine kinase inhibitors.
Cigarette smoke induces aberrant EGF receptor activation that mediates lung cancer development and resistance to tyrosine kinase inhibitors.
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DOI：
10.1158/1535-7163.mct-11-0698
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发表时间：
2012-04
影响因子：
5.7
通讯作者：
Goldkorn T
中科院分区：
文献类型：
--
作者：
Filosto S;Becker CR;Goldkorn T
EGF 受体 (EGFR) 及其下游信号传导与肺癌的发展有关。因此，人们花费了大量精力来开发与 EGFR ATP 袋结合、阻断 EGFR 磷酸化/信号传导的特异性酪氨酸激酶抑制剂 (TKI)。 TKI 的临床使用对 EGFR 激酶结构域发生突变的部分肺癌有效，使受体对 TKI 高度敏感。然而，这些益处是有限的，并且额外 EGFR 突变的出现通常会导致 TKI 耐药和疾病进展。此前，我们证明了一种将香烟烟雾 (CS) 与 EGFR 驱动的肺癌联系起来的机制。具体来说，肺上皮细胞暴露于 CS 诱导的氧化应激会刺激异常的 EGFR 磷酸化/激活，并导致受体泛素化/降解受损。激活受体的异常稳定会导致不受控制的细胞生长和肿瘤发生。在这里，我们首次描述了 EGFR 对 TKI 耐药的新型翻译后机制。气道上皮细胞暴露于 CS 会导致 EGFR 异常磷酸化/激活，从而产生与配体 EGF 诱导的构象不同的构象。与 EGF 激活的 EGFR 不同，CS 激活的 EGFR 结合 c-Src 和 Caveolin-1，并且不发生典型的二聚化。重要的是，CS 激活的 EGFR 不受 TKI（AG1478；厄洛替尼；吉非替尼）的抑制；事实上，即使在 TKI 敏感的 EGFR 突变体中，CS 暴露也会诱导 TKI 耐药。我们的研究结果表明，CS 暴露不仅会刺激异常的 EGFR 磷酸化，从而损害受体降解，还会诱导对 TKI 产生耐药性的不同 EGFR 构象和信号传导。总之，这些发现为 CS 诱导的肺癌发展和 TKI 耐药性提供了新的见解。
The EGF Receptor (EGFR) and its downstream signaling are implicated in lung cancer development. Therefore, much effort was spent in developing specific tyrosine kinase inhibitors (TKIs) that bind to the EGFR ATP-pocket, blocking EGFR phosphorylation/signaling. Clinical use of TKIs is effective in a subset of lung cancers with mutations in the EGFR kinase domain, rendering the receptor highly susceptible to TKIs. However, these benefits are limited, and emergence of additional EGFR mutations usually results in TKI resistance and disease progression. Previously, we demonstrated one mechanism linking cigarette smoke (CS) to EGFR-driven lung cancer. Specifically, exposure of lung epithelial cells to CS-induced oxidative stress stimulates aberrant EGFR phosphorylation/activation with impaired receptor ubiquitination/degradation. The abnormal stabilization of the activated receptor leads to uncontrolled cell growth and tumorigenesis. Here we describe for the first time a novel post-translational mechanism of EGFR resistance to TKIs. Exposure of airway epithelial cells to CS causes aberrant phosphorylation/activation of EGFR, resulting in a conformation that is different from that induced by the ligand EGF. Unlike EGF-activated EGFR, CS-activated EGFR binds c-Src and caveolin-1 and does not undergo canonical dimerization. Importantly, the CS-activated EGFR is not inhibited by TKIs (AG1478; Erlotinib; Gefitinib); in fact, the CS exposure induces TKI-resistance even in the TKI-sensitive EGFR mutants. Our findings demonstrate that CS exposure stimulates not only aberrant EGFR phosphorylation impairing receptor degradation, but also induces a different EGFR conformation and signaling that are resistant to TKIs. Together, these findings offer new insights into CS-induced lung cancer development and TKI resistance.