The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells.
The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells.
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DOI：
10.1126/scisignal.2004155
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发表时间：
2013-08-06
影响因子：
7.3
通讯作者：
Lauffenburger DA
中科院分区：
文献类型：
--
作者：
Meyer AS;Miller MA;Gertler FB;Lauffenburger DA
耐药性、信号传导变化和侵袭表型出现之间的关系已得到充分认识，但其潜在机制尚不清楚。使用应用于癌细胞系百科全书数据库的机器学习分析，我们确定了 AXL（编码上皮间质转化 (EMT) 相关受体酪氨酸激酶 (RTK) AXL 的基因）的表达，可以特别预测对 ErbB 家族受体靶向抑制剂缺乏反应。 EGFR（表皮生长因子受体）的激活反式激活 AXL，这种不依赖于配体的 AXL 活性使 EGFR 诱导的信号转导多样化，进入除 EGFR 单独触发的下游途径之外的其他下游途径。 EGF（表皮生长因子）需要 AXL 介导的信号多样化，从而在 AXL 阳性 TNBC（三阴性乳腺癌）细胞中引发运动反应。使用交联免疫共沉淀测定，我们确定 AXL 与 EGFR、其他 ErbB 受体家族成员、MET（肝细胞生长因子受体）和 PDGFR（血小板源性生长因子受体）相关，但与 IGF1R（胰岛素样生长因子 1 受体）或 INSR（胰岛素受体）无关。根据这些 AXL 相互作用数据，我们预测了 AXL 介导的额外 RTK 信号协同作用，并在细胞中验证了这些预测。这种受体激活的替代机制限制了配体阻断疗法的使用，并表明在获得性耐药后不要停止治疗。此外，所有 AXL 阳性 TNBC 细胞系中 EGFR 和 AXL 靶向抑制剂之间的亚加性相互作用可能表明 EGFR 丰度的增加主要是反式激活介导的信号传导的一种手段。
The relationship between drug resistance, changes in signaling, and emergence of an invasive phenotype is well appreciated, but the underlying mechanisms are not well understood. Using machine learning analysis applied to the Cancer Cell Line Encyclopedia database, we identified expression of AXL, the gene that encodes the epithelial-to-mesenchymal transition (EMT)–associated receptor tyrosine kinase (RTK) AXL, as exceptionally predictive of lack of response to ErbB family receptor–targeted inhibitors. Activation of EGFR (epidermal growth factor receptor) transactivated AXL, and this ligand-independent AXL activity diversified EGFR-induced signaling into additional downstream pathways beyond those triggered by EGFR alone. AXL-mediated signaling diversification was required for EGF (epidermal growth factor)–elicited motility responses in AXL-positive TNBC (triple-negative breast cancer) cells. Using cross-linking coimmunoprecipitation assays, we determined that AXL associated with EGFR, other ErbB receptor family members, MET (hepatocyte growth factor receptor), and PDGFR (platelet-derived growth factor receptor) but not IGF1R (insulin-like growth factor 1 receptor) or INSR (insulin receptor). From these AXL interaction data, we predicted AXL-mediated signaling synergy for additional RTKs and validated these predictions in cells. This alternative mechanism of receptor activation limits the use of ligand-blocking therapies and indicates against therapy withdrawal after acquired resistance. Further, subadditive interaction between EGFR- and AXL-targeted inhibitors across all AXL-positive TNBC cell lines may indicate that increased abundance of EGFR is principally a means to transactivation-mediated signaling.