Combined Methylome and Transcriptome Analyses Reveals Potential Therapeutic Targets for EGFR Wild Type Lung Cancers with Low PD-L1 Expression.
Combined Methylome and Transcriptome Analyses Reveals Potential Therapeutic Targets for EGFR Wild Type Lung Cancers with Low PD-L1 Expression.
复制标题
DOI：
10.3390/cancers12092496
复制
发表时间：
2020-09-03
期刊：
影响因子：
5.2
通讯作者：
Wan Y
中科院分区：
文献类型：
--
作者：
Hu W;Wang G;Yarmus LB;Wan Y
低表达的程序性死亡配体1 (PD-L1)，表皮生长因子受体（EGFR）野生型非小细胞肺癌（nsclc）是难治性的，只有很少的治疗选择。本研究旨在阐明这一特殊亚型NSCLC的分子基础，寻找潜在的治疗靶点。我们整合了多个来源的数据，包括转录组、甲基组和临床结果，以揭示表观遗传变化对这种特殊亚型肺癌的影响。我们阐明了异常甲基化和相关的异常基因表达，并将新出现的甲基化转录模式分类为HypoUp、HypoDown、HyperUp或HyperDown。我们发现异常的甲基化转录模式显著影响患者的总体生存时间。我们使用蛋白质-药物相互作用数据和分子对接分析来确定潜在的治疗候选药物。这项研究揭示了这种特殊亚型肺癌的独特甲基化转录特征，并提供了一种适应性强的方法来识别潜在的治疗靶点。靶向PD-1/PD-L1的免疫检查点抑制剂（ICIs）在晚期非小细胞肺癌（NSCLC）中显示出显著的治疗效果。然而，低表达的程序性死亡配体1 （PD-L1）、表皮生长因子受体（EGFR）野生型非小细胞肺癌是难治性的，只有很少的治疗选择。目前，为了提高治疗反应率，经常使用ICIs联合治疗。然而，该方案仍然与不良的治疗结果相关。因此，迫切需要确定这一亚群NSCLC的潜在治疗靶点。在这里，我们报告了这个特殊亚群的不同甲基化特征。此外，还偶然发现了一些靶向治疗的可药物靶点和相关药物。我们发现三个区域（TSS200、TSS1500和基因体）的高甲基化差异甲基化区域（DMRs）显著高于低甲基化区域。发现下调的甲基化基因参与免疫应答和T细胞介导的免疫的负调控。此外，4个甲基化基因（PLCXD3（磷脂酰肌醇特异性磷脂酶C， X结构域含3）、BAIAP2L2 （BAR/IMD结构域含Adaptor Protein 2 Like 2）、NPR3（利钠肽受体3）、SNX10（分选连接蛋白10））的表达可以影响患者的预后。随后，基于DrugBank数据，使用NetworkAnalyst 3.0对上调的差异甲基化基因进行蛋白-药物相互作用分析。9个基因的蛋白产物被鉴定为潜在的可药物靶点，其中XDH（黄嘌呤脱氢酶）、ATIC（5-氨基吡唑-4-羧酰胺核糖核苷酸甲酰转移酶/IMP环水解酶）、CA9（碳酸酐酶9）、SLC7A11（溶质载体家族7成员11）和GAPDH（甘油醛-3-磷酸脱氢酶）的致瘤潜力已在前期研究中得到证实。下一步，进行分子对接和分子动力学模拟，验证治疗靶点的结构基础。值得注意的是，已确定的靶向ATIC的培美曲塞最近已被批准与抗pd1抑制剂联合用于一线治疗肺癌，无论PD-L1表达如何。在未来的工作中，将启动一项关键的临床研究来进一步验证我们的发现。
Low expression of programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLCs) are refractory, and only few therapeutic options exist. This study aims to clarify the molecular basis of this special subtype of NSCLC and identify potential therapeutic targets. We performed integrating data from multiple sources including transcriptome, methylome, and clinical outcome to uncover the effect of epigenetic changes acting this special subtype lung cancer. We elucidated both aberrant methylation and associated aberrant gene expression and the emerging methylation-transcription patterns were classified as HypoUp, HypoDown, HyperUp, or HyperDown. We found that the aberrant methylation-transcription patterns significantly affect the overall survival time of the patients. We used protein–drug interaction data and molecular docking analysis to identify potential therapeutic candidates. This study uncovered the distinct methylation-transcription characteristics of this special subtype lung cancer, and provided an adaptable way to identify potential therapeutic targets. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have demonstrated remarkable treatment efficacy in advanced non-small cell lung cancer (NSCLC). However, low expression of programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) wild-type NSCLCs are refractory, and only few therapeutic options exist. Currently, combination therapy with ICIs is frequently used in order to enhance the treatment response rates. Yet, this regimen is still associated with poor treatment outcome. Therefore, identification of potential therapeutic targets for this subgroup of NSCLC is strongly desired. Here, we report the distinct methylation signatures of this special subgroup. Moreover, several druggable targets and relevant drugs for targeted therapy were incidentally identified. We found hypermethylated differentially methylated regions (DMRs) in three regions (TSS200, TSS1500, and gene body) are significantly higher than hypomethylated ones. Downregulated methylated genes were found to be involved in negative regulation of immune response and T cell-mediated immunity. Moreover, expression of four methylated genes (PLCXD3 (Phosphatidylinositol-Specific Phospholipase C, X Domain Containing 3), BAIAP2L2 (BAR/IMD Domain Containing Adaptor Protein 2 Like 2), NPR3 (Natriuretic Peptide Receptor 3), SNX10 (Sorting Nexin 10)) can influence patients’ prognosis. Subsequently, based on DrugBank data, NetworkAnalyst 3.0 was used for protein–drug interaction analysis of up-regulated differentially methylated genes. Protein products of nine genes were identified as potential druggable targets, of which the tumorigenic potential of XDH (Xanthine Dehydrogenase), ATIC (5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase), CA9 (Carbonic Anhydrase 9), SLC7A11 (Solute Carrier Family 7 Member 11), and GAPDH (Glyceraldehyde-3-Phosphate Dehydrogenase) have been demonstrated in previous studies. Next, molecular docking and molecular dynamics simulation were performed to verify the structural basis of the therapeutic targets. It is noteworthy that the identified pemetrexed targeting ATIC has been recently approved for first-line use in combination with anti-PD1 inhibitors against lung cancer, irrespective of PD-L1 expression. In future work, a pivotal clinical study will be initiated to further validate our findings.
登录
查看更多内容
DOI：
10.1126/science.aaw9872
发表时间：
2020-04-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badgley MA;Kremer DM;Maurer HC;DelGiorno KE;Lee HJ;Purohit V;Sagalovskiy IR;Ma A;Kapilian J;Firl CEM;Decker AR;Sastra SA;Palermo CF;Andrade LR;Sajjakulnukit P;Zhang L;Tolstyka ZP;Hirschhorn T;Lamb C;Liu T;Gu W;Seeley ES;Stone E;Georgiou G;Manor U;Iuga A;Wahl GM;Stockwell BR;Lyssiotis CA;Olive KP
通讯作者：
Olive KP
影响因子：
20.4
作者：
He, Yayi;Yu, Hui;Hirsch, Fred R.
通讯作者：
Hirsch, Fred R.
影响因子：
5.2
作者：
Aljaibeji, Hayat;Mukhopadhyay, Debasmita;Taneera, Jalal
通讯作者：
Taneera, Jalal
从头表观遗传程序抑制PD-1封锁介导的T细胞再生。
影响因子：
64.5
作者：
Ghoneim HE;Fan Y;Moustaki A;Abdelsamed HA;Dash P;Dogra P;Carter R;Awad W;Neale G;Thomas PG;Youngblood B
通讯作者：
Youngblood B
影响因子：
3.6
作者：
Hsieh, Yi-Ching;Tedeschi, Philip;Abali, Emine Ercikan
通讯作者：
Abali, Emine Ercikan