Abstract
Simple SummaryLow 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.
Highlights
Tyrosine kinase inhibitors (TKI) have shown remarkable benefits against lung cancer, they are not effective for epidermal growth factor receptor (EGFR) mutation-negative patients.More recently, the introduced immune checkpoint inhibitors (ICIs) therapy has shown marked clinical responses, especially effective towards these cases [1,2,3,4]
The results indicated that aberrant methylation-transcription patterns significantly affect the overall survival time of the patients since a risk assessment model including four differentially methylated and expressed genes
Patients with “EGFR Wild Type/Low programmed death-ligand 1 (PD-L1) expression” lung cancer lack a first-line single drug therapy as they hardly respond to tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors
Summary
Tyrosine kinase inhibitors (TKI) have shown remarkable benefits against lung cancer, they are not effective for epidermal growth factor receptor (EGFR) mutation-negative patients.More recently, the introduced immune checkpoint inhibitors (ICIs) therapy has shown marked clinical responses, especially effective towards these cases [1,2,3,4]. Tyrosine kinase inhibitors (TKI) have shown remarkable benefits against lung cancer, they are not effective for epidermal growth factor receptor (EGFR) mutation-negative patients. In the KEYNOTE 024 phase III trial, pembrolizumab, an anti-programmed death 1 (PD1) antibody, showed better therapeutic effect than standard chemotherapy against EGFR wild type lung cancers overexpressing programmed death-ligand 1 (PD-L1) [5]. 42 trial [6] which included any PD-L1 positive non-small cell lung cancer (NSCLC) patients led to the approval of pembrolizumab as the first-line single agent for the treatment of metastatic NSCLC. Regimens combining PD-1/PD-L1 blockade with other approaches, including chemotherapy, have been created with the aim of enhancing response rates. In the KEYNOTE 021 study, combining chemotherapy with pembrolizumab increased overall response rate by about 57% relative to chemotherapy alone (13%) in cases exhibiting low PD-L1 levels. Other approved combination regimens involve inhibitors of vascular endothelial growth factor (VEGF) [10] and cytotoxic
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