Phospholipids of tumor extracellular vesicles stratify gefitinib-resistant nonsmall cell lung cancer cells from gefitinib-sensitive cells.
Phospholipids of tumor extracellular vesicles stratify gefitinib-resistant nonsmall cell lung cancer cells from gefitinib-sensitive cells.
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DOI：
10.1002/pmic.201400243
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发表时间：
2015-02
期刊：
影响因子：
3.4
通讯作者：
Kim KP
中科院分区：
文献类型：
--
作者：
Jung JH;Lee MY;Choi DY;Lee JW;You S;Lee KY;Kim J;Kim KP
表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKIs)，如吉非替尼，是非小细胞肺癌(NSCLC)患者的黄金标准治疗方案之一，这些患者最终由于获得性耐药而失败，并因EGFR中T790M等次级激活突变的发展而复发。预测癌症患者的化疗反应是化疗中的一大挑战。本研究的目的是确定肿瘤细胞外小泡(EV)的磷脂特征是否与非小细胞肺癌的吉非替尼耐药有关。采用基于MS的鸟枪法对吉非替尼耐药(PC9R)和应答(PC9)NSCLC细胞及其脱落的EV进行了深入的分析。脂质MALDI-MS分析表明，与PC9细胞相比，PC9R细胞中EV的磷脂组成明显不同。随后的统计分析发现了35种(20种正离子模式和15种负离子模式)差异调节的脂类，与PC9 EV相比，它们在PC9R EV中显著过度表达或表达不足(p值和lt；0.01，倍数变化>；1.5)。我们的磷脂特征表明，EV与药物敏感性有关，这值得进一步研究，以评估接受抗EGFR TKI治疗的非小细胞肺癌患者的化疗耐药性。
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib are one of gold standard treatment options for nonsmall-cell lung cancer (NSCLC) patients, which eventually fail due to the acquired resistance and relapse because of the development of secondary activating mutations such as T790M in EGFR. Predicting chemo-responsiveness of cancer patients provides a major challenge in chemotherapy. The goal of the present study is to determine whether phospholipid signatures of tumor extracellular vesicles (EV) are associated with gefitinib-resistance of NSCLC. A sophisticated MS-based shotgun lipidomic assays were performed for in-depth analysis of the lipidomes of gefitinib-resistant (PC9R) and responsive (PC9) NSCLC cells and their shed EV from these cell lines (PC9EV or PC9REV). Lipid MALDI-MS analysis showed that EV phospholipid composition was significantly distinct in PC9R, compared to PC9 cells. Following statistical analyses has identified 35 (20 positive and 15 negative ion mode) differentially regulated lipids, which are significantly over- or underexpressed in PC9R EV, compared to PC9 EV (p value < 0.01, fold change > 1.5). Our phospholipid signatures suggest that EV associates with drug sensitivity, which is worthy of additional investigation to assess chemoresistance in patients with NSCLC treated with anti-EGFR TKIs.