Surfactant protein D inhibits activation of non-small cell lung cancer-associated mutant EGFR and affects clinical outcomes of patients
Surfactant protein D inhibits activation of non-small cell lung cancer-associated mutant EGFR and affects clinical outcomes of patients
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DOI：
10.1038/onc.2017.253
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发表时间：
2017-11-16
期刊：
影响因子：
8
通讯作者：
Takahashi, M.
中科院分区：
文献类型：
--
作者：
Umeda, Y.;Hasegawa, Y.;Takahashi, M.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）敏感和TKI耐药突变与肺腺癌相关。EGFR突变体先前显示出配体非依赖性激活。我们以前已经证明，肺表面活性物质蛋白D（SP-D，SFTPD）抑制野生型EGFR信号通过阻断配体结合EGFR。我们在此证明，SFTPD下调携带EGFR突变（如TKI敏感性外显子19缺失（Ex 19 del）和L 858 R突变以及TKI耐药T790 M突变）的细胞中的配体非依赖性信号传导，随后抑制细胞生长和运动。肺癌细胞系中的凝集素印迹和配体印迹表明EGFR突变体表达寡聚甘露糖型N-聚糖，并与SFTPD直接相互作用。交联实验表明，SFTPD抑制EGFR突变体的配体非依赖性二聚化。我们还证明，SFTPD减少二聚化独立的磷酸化Ex 19 del和T790 M EGFR突变体使用点突变，破坏不对称二聚体界面。证实SFTPD增强了EGFR-TKI的活力抑制作用。此外，对121例肺腺癌患者进行回顾性分析，以检查血清SFTPD水平与临床结局之间的相关性，结果表明，在接受TKI治疗的携带EGFR突变（包括Ex 19 del或L 858 R）的肺癌患者中，高血清SFTPD水平与远处转移数量减少以及总生存期和无进展生存期延长相关。这些发现表明，SFTPD下调TKI敏感和耐药EGFR突变体信号传导，SFTPD水平与临床结局相关。这些发现说明血清SFTPD水平可作为评估EGFR-TKI疗效的潜在标志物。
Tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant mutations of epidermal growth factor receptor (EGFR) are associated with lung adenocarcinoma. EGFR mutants were previously shown to exhibit ligand-independent activation. We have previously demonstrated that pulmonary surfactant protein D (SP-D, SFTPD) suppressed wild-type EGFR signaling by blocking ligand binding to EGFR. We herein demonstrate that SFTPD downregulates ligand-independent signaling in cells harboring EGFR mutations such as TKI-sensitive exon 19 deletion (Ex19del) and L858R mutation as well as TKI-resistant T790M mutation, subsequently suppressing cellular growth and motility. Lectin blotting and ligand blotting in lung cancer cell lines suggested that EGFR mutants express oligomannose-type N-glycans and interact with SFTPD directly. Cross-linking assay indicated that SFTPD inhibits ligand-independent dimerization of EGFR mutants. We also demonstrated that SFTPD reduced dimerization-independent phosphorylation of Ex19del and T790M EGFR mutants using point mutations that disrupted the asymmetric dimer interface. It was confirmed that SFTPD augmented the viability-suppressing effects of EGFR-TKIs. Furthermore, retrospective analysis of 121 patients with lung adenocarcinoma to examine associations between serum SFTPD levels and clinical outcome indicated that in TKI-treated patients with lung cancer harboring EGFR mutations, including Ex19del or L858R, high serum SFTPD levels correlated with a lower number of distant metastases and prolonged overall survival and progression-free survival. These findings suggest that SFTPD downregulates both TKI-sensitive and -resistant EGFR mutant signaling, and SFTPD level is correlated with clinical outcome. These findings illustrate the use of serum SFTPD level as a potential marker to estimate the efficacy of EGFR-TKIs.