期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 20, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/ijms20102515
关键词
EGFR; tyrosine kinase inhibitor; dimerization; palmitoylation; kinase-independent function; resistance
Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small molecule tyrosine kinase inhibitors (TKIs) is often ineffective in treating cancers harboring wild-type EGFR (wt-EGFR). TKIs are known to cause dimerization of EGFR without altering its expression level. Given the fact that EGFR possesses kinase-independent pro-survival function, the role of TKI-inactivated EGFR in cancer cell survival needs to be addressed. In this study, using wt-EGFR-expressing cancer cells A549 (lung), DU145 (prostate), PC3 (prostate), and MDA-MB-231 (breast), we characterized the TKI-induced dimerization status of EGFR and determined the dependency of cells on kinase-inactivated EGFR for survival. We report that TKI-induced EGFR dimerization is dependent on palmitoylation and independent of its kinase activity, and that mutations of the cysteine residues known to be critical for EGFR's palmitoylation abolished TKI-induced EGFR dimerization. Furthermore, TKI-induced EGFR dimerization is persistent in TKI-resistant cells, and inhibition of palmitoylation by 2-bromopalmitate, or targeted reduction of the kinase-inactivated EGFR by siRNA or by an EGFR-downregulating peptide, are lethal to TKI-resistant cancer cells. This study suggests that kinase-inactivated EGFR remains to be a viable therapeutic target for wt-EGFR cancers and that inhibiting palmitoylation or downregulating EGFR may overcome TKI resistance.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据