Identification of Hub Genes and Small Molecule Drugs Associated with Acquired Resistance to Gefitinib in Non-Small Cell Lung Cancer

Abstract

Targeting EGFR, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), brings lights to the treatment of non-small cell lung cancer (NSCLC). Although T790M mutation responded as one of the main reasons of acquired resistance, still 15% of the resistance patients can't be explained by the known mechanisms. The purpose of this research was to identify some new mechanisms of gefitinib acquired resistance, and to predict small molecules drugs which may reverse drug resistance by integrated bioinformatics analysis. The GSE34228 data package containing the microarray data of acquired gefitinib-resistant cell line (PC9GR) and gefitinib-sensitive cell line (PC9) from the GEO database were downloaded, and gene co-expression networks by weighted gene co-expression network analysis (WGCNA) were constructed to identified key modules and key genes related to gefitinib resistance. Furthermore, the significantly differentially expressed genes (DEGs) between the two cell types were screened out, and a protein-protein interaction (PPI) network to obtain the key genes of DEGs was accordingly constructed. Through the above two methods, 4 hub genes, PI3, S100A8, AXL and PNPLA4 were mined as the most relevant to gefitinib resistance. Among them, PI3, S100A8 were down-regulated in PC9GR cell samples, while AXL, PNPLA4 were up-regulated. The gene set enrichment analysis (GSEA) for single gene showed that the four hub genes were mainly correlated with cell proliferation and cycle. Besides, small molecule drugs with the potential to overcome resistance, such as Emetine and cephaeline, were screened by CMap database. Consistent with this, in vitro experiments results have shown that emetine and cephaeline can increase the sensitivity of drug-resistant cells to gefitinib, and the mechanism may be related to the regulation of PI3 and S100A8. In conclusion, 4 hub genes were found to be related to the occurrence of gefitinib resistance in non-small cell lung cancer, and several small molecule drugs were screened out as potential therapeutic agents to overcome gefitinib resistance, which may lead a new way for the treatment of NSCLC of acquired resistance to gefitinib.

Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer

“…Although most naïve mt EGFR -expressing NSCLC cells are initially sensitive to EGFR TKI treatment [ 15 , 17 , 187 , 188 ], acquired resistance eventually happens [ 189 , 190 , 191 , 192 , 193 , 194 , 195 ] and AXL and/or GAS6 are frequently upregulated [ 53 , 58 , 196 , 197 ]. Other mechanisms that drive secondary resistance to EGFR TKIs are summarized in Table 1 .…”

“…Other mechanisms that drive secondary resistance to EGFR TKIs are summarized in Table 1 . MERTK and AXL are co-expressed with EGFR in NSCLC [ 58 , 69 , 80 ], and both receptors, but especially AXL, have been studied as causative drivers of secondary EGFR TKI resistance in mt EGFR -expressing NSCLCs [ 53 , 70 , 112 , 196 ]. Forced expression of an active form of AXL, but not a kinase-impaired AXL, in erlotinib-sensitive tumor cells was sufficient to induce erlotinib resistance [ 53 ].…”

Repurposing glucocorticoids as adjuvant reagents for immune checkpoint inhibitors in solid cancers

“…Drug repurposing research highly relies on bioinformatics and chemical informatics 5 . Recently, Li et al 6 characterized the mechanisms of acquired resistance to gefitinib in non-small cell lung cancer. They analyzed microarray data of an acquired gefitinib-resistant cell line (PC9GR) and a gefitinib-sensitive cell line (PC9), and constructed a differentially expressed gene set.…”

“…Using CMap database screening, small molecule drugs with the potential to overcome drug resistance, such as emetine and cephaeline, were found to increase the sensitivity to gefitinib. The molecular mechanism may be related to the regulation of PI3 and S100A8 6 . Xiang et al 1 also adopted this strategy; they identified a group of compounds that may simultaneously inhibit PD-L1 and IDO1, and among them, dexamethasone was the optimal drug.…”

Applications of Machine Learning to Predict Cisplatin Resistance in Lung Cancer

“…For patients with mutations in the epidermal growth factor receptor (EGFR), acquired resistance will inevitably occur when they receive a first-generation EGFR tyrosine kinase inhibitor (TKI; eg, gefitinib) or a third-generation EGFR TKI (eg, osimertinib) that overcomes the EGFR T790M mutation. 9 Immunotherapy has antitumor effects in a small part of the population, while it may cause serious immune-related adverse reactions in some people. For patients who do not meet the criteria for the above treatments or for patients who have failed previous immunotherapy or targeted therapy, systemic treatments including cisplatin are still important.…”