T790米
生物
癌症研究
表面活性蛋白D
肺癌
表皮生长因子受体
腺癌
突变体
分子生物学
癌症
吉非替尼
受体
内科学
生物化学
医学
基因
遗传学
先天免疫系统
作者
Yasuaki Umeda,Yoshihiro Hasegawa,Mitsuo Otsuka,Shigeru Ariki,Rina Takamiya,Atsushi Saito,Yasuaki Uehara,Hiroshi Shinmoto,Koji Kuronuma,Hirofumi Chiba,Hirofumi Ohnishi,Yoshiki Sakuma,Hiroki Takahashi,Yoshio Kuroki,Motoko Takahashi
出处
期刊:Oncogene
[Springer Nature]
日期:2017-07-24
卷期号:36 (46): 6432-6445
被引量:24
摘要
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.
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