Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5
Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5
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DOI：
10.7150/thno.29093
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Pages, Gilles
中科院分区：
文献类型：
--
作者：
Giuliano, Sandy;Dufies, Maeva;Pages, Gilles
促溶剂如舒尼替尼、拉帕替尼和氯喹属于更常用于治疗晚期癌症的药物家族。舒尼替尼是转移性肾细胞癌（mRCC）的标准治疗，拉帕替尼用于曲妥珠单抗/帕妥珠单抗难治性癌症。然而，患者不可避免地复发，延迟从几个月到几年不等。为了改善复发前的反应性，必须确定导致这种变异性的机制。我们以前表明，舒尼替尼成为隔离在溶酶体中，因为其基本pKa.Methods：修改基因表达的舒尼替尼和舒尼替尼耐药细胞进行了分析，转录组学和蛋白质组学分析。通过FACS评估ROS产生。用报告基因评价了炎症基因表达的核因子κ B（NF κ B）依赖性转录调控。使用在线可用数据库（TCGA）并使用参加SUVEGIL临床试验（NCT 00943839）的患者队列分析CXCL 5与存活率的相关性。结果：我们现在表明，舒尼替尼在溶酶体中的隔离诱导不完全的自噬过程，导致NF κ B炎症通路的激活。我们定义了一个亚组的炎症细胞因子，在急性或慢性刺激后被药物上调。舒尼替尼耐药细胞中上调最多的基因之一是CXCL 5细胞因子。CXCL 5也在RCC中由氯喹诱导，并且在用拉帕替尼急性或慢性治疗后的HER 2阳性乳腺癌细胞系模型中诱导。CXCL 5与RCC中较短的生存期和最具侵袭性的乳腺癌形式相关。舒尼替尼治疗的患者的血浆中存在的CXCL 5的水平预测舒尼替尼的疗效，但不是VEGF定向抗体bevacizumab.Conclusion：这项翻译研究确定CXCL 5作为生物标志物的lysosomotropic药物的疗效，个性化医疗的潜在资产。
Lysosomotropic agents such as sunitinib, lapatinib, and chloroquine belong to a drug family that is being used more frequently to treat advanced cancers. Sunitinib is standard care for metastatic renal cell carcinomas (mRCC) and lapatinib is used for trastuzumab/pertuzumab-refractory cancers. However, patients ineluctably relapse with a delay varying from a few months to a few years. To improve reactivity prior to relapse it is essential to identify the mechanisms leading to such variability. We showed previously that sunitinib became sequestered in lysosomes because of its basic pKa.Methods: Modifications to gene expression in response to sunitinib and in sunitinib resistant cells were analyzed by transcriptomic and proteomic analysis. ROS production was evaluated by FACS. Nuclear Factor kappa B (NFkB)-dependent transcriptional regulation of inflammatory gene expression was evaluated with a reporter gene. Correlation of CXCL5 with survival was analyzed with an online available data base (TCGA) and using a cohort of patients enrolled in the SUVEGIL clinical trial (NCT00943839).Results: We now show that sunitinib sequestration in lysosomes induced an incomplete autophagic process leading to activation of the NFkB inflammatory pathway. We defined a subset of inflammatory cytokines that were up-regulated by the drug either after an acute or chronic stimulus. One of the most up-regulated genes in sunitinib-resistant cells was the CXCL5 cytokine. CXCL5 was also induced in RCC by chloroquine and in a model of HER2 positive breast cancer cell lines after acute or chronic treatment with lapatinib. CXCL5 correlated to shorter survival in RCC and to the most aggressive forms of breast cancers. The levels of CXCL5 present in the plasma of patients treated with sunitinib were predictive of the efficacy of sunitinib but not of the VEGF-directed antibody bevacizumab.Conclusion: This translational study identified CXCL5 as a biomarker of efficacy of lysosomotropic drugs, a potential asset for personalized medicine.