Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival
Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival
复制标题
DOI：
10.1158/0008-5472.can-05-4620
复制
发表时间：
2006-06-01
期刊：
影响因子：
11.2
通讯作者：
Haura, Eric B.
中科院分区：
文献类型：
--
作者：
Song, Lanxi;Morris, Mark;Haura, Eric B.
表皮生长因子受体（EGFR）的突变选择性地激活Akt和信号转导和转录激活因子（STAT）通路，这些通路在肺癌细胞存活中起重要作用。Src家族激酶可以与受体酪氨酸激酶合作，通过下游分子，如磷脂酰肌醇3-激酶/PTEN/Akt和STATs发出信号。基于EGFR信号在肺癌中的重要性，已知的EGFR和Src蛋白之间的合作，以及人类肺癌中Src活性升高的证据，我们评估了一种新型口服生物可用的Src抑制剂达沙替尼（BMS-324825）在具有明确EGFR状态的肺癌细胞系中的有效性。在这里，我们表明暴露于达沙替尼的肺癌细胞的细胞命运（死亡与生长停滞）依赖于EGFR状态。在依赖EGFR存活的EGFR突变细胞中，达沙替尼通过诱导细胞凋亡降低细胞活力，而对野生型（WT） EGFR细胞系的凋亡作用最小。这些egfr突变细胞系的凋亡诱导与活化的Akt和STAT3存活蛋白的下调相对应。在对EGFR抑制不敏感的WT或耐药EGFR突变细胞系中，达沙替尼诱导G(1)细胞周期阻滞，伴有细胞周期蛋白D和p27蛋白的相关变化，抑制活化的FAK，并阻止肿瘤细胞侵袭。我们的研究结果表明，达沙替尼可以通过破坏细胞生长、存活和肿瘤侵袭来有效治疗肺癌患者。我们的研究结果表明，EGFR状态在决定细胞对达沙替尼反应的命运中是重要的。
Mutations of the epidermal growth factor receptor (EGFR) selectively activate Akt and signal transducer and activator of transcription (STAT) pathways that are important in lung cancer cell survival. Src family kinases can cooperate with receptor tyrosine kinases to signal through downstream molecules, such as phosphatidylinositol 3-kinase/PTEN/Akt and STATs. Based on the importance of EGFR signaling in lung cancer, the known cooperation between EGFR and Src proteins, and evidence of elevated Src activity in human lung cancers, we evaluated the effectiveness of a novel orally bioavailable Src inhibitor dasatinib (BMS-324825) in lung cancer cell lines with defined EGFR status. Here, we show that cell fate (death versus growth arrest) in lung cancer cells exposed to dasatinib is dependent on EGFR status. In cells with EGFR mutation that are dependent on EGFR for survival, dasatinib reduces cell viability through the induction of apoptosis while having minimal apoptotic effect on cell lines with wild-type (WT) EGFR. The induction of apoptosis in these EGFR-mutant cell lines corresponds to down-regulation of activated Akt and STAT3 survival proteins. In cell lines with WT or resistant EGFR mutation that are not sensitive to EGFR inhibition, dasatinib induces a G(1) cell cycle arrest with associated changes in cyclin D and p27 proteins, inhibits activated FAK, and prevents tumor cell invasion. Our results show that dasatinib could be effective therapy for patients with lung cancers through disruption of cell growth, survival, and tumor invasion. Our results suggest EGFR status is important in deciding cell fate in response to dasatinib.