Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients
Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients
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STAT1 多态性对克唑替尼诱导的 ALK 阳性非小细胞肺癌患者肝毒性的影响
DOI：
10.1007/s00432-020-03476-4
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发表时间：
2021-01
影响因子：
3.6
通讯作者：
Chen Likun
中科院分区：
文献类型：
--
作者：
Xin Shuang;Fang Wenfeng;Li Jianwen;Li Delan;Wang Changzheng;Huang Quanfei;Huang Min;Zhuang Wei;Wang Xueding;Chen Likun
目的克唑替尼是治疗ALK阳性非小细胞肺癌的一线小分子酪氨酸激酶抑制剂。本研究采用回顾性药物基因组学研究方法，探讨ALK阳性NSCLC患者中RTK下游信号通路相关基因与克唑替尼肝毒性的关系。使用EnrichR进行KEGG和反应组途径富集分析。使用R包DESeq 2在克唑替尼敏感组和耐药组之间的CCLE肝源细胞系中鉴定差异表达基因。2012年至2015年，42例NSCLC患者入组本研究。使用Sequenom Massarray系统对90个多态性进行基因分型。测序ofHGFR（c-Met）基因进行了离子激流Proton.ResultsIn总数，66.7%的NSCLC患者患有克唑替尼诱导的肝毒性和11.9%的进展为严重的肝毒性。分类回归随机森林模型中最重要的特征集中在RTK下游信号通路（JAK/STAT、RAS/RAF/MAPK、PI 3 K/AKT通路）和免疫系统相关通路。与MAPK-ERK信号通路密切相关的胶原蛋白家族基因（COL 1A 1、COL 1A 2、COL 6A 1、COL 5A 1）和其他细胞外基质蛋白（TNC、TAGLN、TENM 2、EDIL 3、VCAN、CNN 1、SH 3BP 4、TAGLN）在克唑替尼耐药细胞系中显著富集。多因素Logistic回归分析显示，STAT 1 rs 10208033（T > C）与克唑替尼肝毒性显著相关（OR = 6.733，95%CI 1.406- 32.24，P = 0.017）。与非CC基因型相比，STAT 1 rs 10208033 CC基因型发生克唑替尼肝毒性的OR为5.5（95%CI 1.219- 24.81，P = 0.027）。在人胎肝细胞系L-02中进一步的细胞活力测试表明，STAT 1抑制剂可能保护肝细胞免受crizotinib. Conclusionrs 10208033多态性引起的毒性，是一个潜在的生物标志物预测crizotinib诱导的肝毒性。这些结果表明STAT 1在克唑替尼诱导的肝毒性中起重要作用。需要进一步的研究来证实我们的发现并了解潜在的机制。
PurposeCrizotinib is the first-line small molecule tyrosine kinase inhibitor forALK-positive non-small cell lung cancer. In this study, a retrospective pharmacogenomics investigation was conducted to explore the relationship between genes related to RTK downstream signaling pathways and crizotinib-induced hepatic toxicity inALK-positive NSCLC patients.MethodsThe variable importance analysis of random forest algorithm was applied to identify the significant features which contribute to the crizotinib sensitivity in Cancer Cell Line Encyclopedia (CCLE) database. The KEGG and reactome pathway enrichment analysis were conducted with EnrichR. The differential expression genes were identified with R package DESeq2 in CCLE liver derived cell lines between crizotinib sensitive and resistant groups. From 2012 to 2015, 42 NSCLC patients were enrolled in this study. 90 polymorphisms were genotyped using the Sequenom Massarray system. Sequencing ofHGFR(c-Met) genes was carried out on the Ion Torrent Proton.ResultsIn total, 66.7% NSCLC patients suffered from crizotinib-induced liver toxicity and 11.9% progressed to severe hepatic toxicity. The features with the top importance from classification and regression random forest model were enriched in RTK downstream signaling pathways (JAK/STAT, RAS/RAF/MAPK, PI3K/AKTpathways) and immune system-related pathways. Collagen family genes (COL1A1, COL1A2, COL6A1, COL5A1) and other extracellular matrix protein (TNC, TAGLN, TENM2, EDIL3, VCAN, CNN1, SH3BP4, TAGLN), which were closely related to MAPK-ERK signaling pathways, were significantly enriched in crizotinib resistant cell lines. In multiple logistic regression, STAT1 rs10208033 (T > C) was significantly associated with crizotinib-induced liver toxicity (OR = 6.733, 95% CI 1.406–32.24,P= 0.017). Compared with non-CC, OR is 5.5 (95% CI 1.219–24.81,P= 0.027) forSTAT1rs10208033 CC genotype to develop crizotinib-induced liver toxicity. Further cell viability test in human fetal hepatocyte line, L-02, reveals that the STAT1 inhibitor might protect hepatocyte cells from the toxicity caused by crizotinib.ConclusionPolymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest thatSTAT1plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
0.6
作者：
K. Chalupský;I. Kanchev;O. Zbodakova;H. Buryová;M. Jiroušková;V. Kořínek;M. Gregor;R. Sedláček
通讯作者：
K. Chalupský;I. Kanchev;O. Zbodakova;H. Buryová;M. Jiroušková;V. Kořínek;M. Gregor;R. Sedláček
影响因子：
158.5
作者：
Solomon, Benjamin J.;Mok, Tony;Waqar, S.
通讯作者：
Waqar, S.
影响因子：
5.8
作者：
Kazandjian, Dickran;Blumenthal, Gideon M.;Pazdur, Richard
通讯作者：
Pazdur, Richard
影响因子：
3.4
作者：
Jung, Dasom;Han, Ji Min;Gwak, Hye Sun
通讯作者：
Gwak, Hye Sun