SIRT2, TFEB, CNIH3, ADRM1, AND TM9SF4 AS POTENTIAL BIOMARKERS OF RESISTANCE TO CRIZOTINIB AND POOR PROGNOSIS IN LUNG ADENOCARCINOMA: IMPLICATIONS FOR TARGETED THERAPY AND IMMUNOTHERAPY

Abstract

BackgroundLung adenocarcinoma (LUAD) with ALK mutations benefits from targeted treatment with ALK tyrosine kinase inhibitors, such as crizotinib. This therapy has been shown to be more effective than traditional chemotherapy, with improved tolerance in patients. However, resistance to crizotinib can develop, limiting its long-term efficacy. The aim of this study is to identify deregulated genes in crizotinib-resistant ALK-mutated lung adenocarcinoma cell lines. This will allow us to select patients who are more likely to benefit from crizotinib and help design new therapeutic strategies to overcome resistance, ultimately leading to better clinical outcomes. MethodsAn in silico study using genomic data from crizotinib-sensitive and crizotinib-resistant LUAD cells was conducted. Through statistical analysis, genes with differential expression in crizotinib resistant cells were identified. These genes were classified by their biological function using Enrichr, and those with the highest amplification frequency according to cBIOPORTAL were selected. Next, gene expression association with prognosis and with immune cell infiltration were investigated using Kaplan-Meier plotter and TIMER databases, respectively. Gene expression analysis in normal and tumoral tissues was explored using TNM plot and potential therapeutic agents against the identified targets were identified from several databases. ResultsWe found 9 genes overexpressed in resistant LUAD cells, with statistically significant cell function, to be amplified and associated with poor prognosis. Among them, SIRT2, TFEB, TMPSF4, CINH3 and ADRM1 display an immunosuppressed TME and TMPSF4, CINH3 and ADRM1 are overexpressed in tumoral tissue. Some of them, such as SIRT2, have therapeutic agents already approved in other context (gefitinib in EFGR mutated lung cancer). We identified nine genes that are overexpressed in crizotinib-resistant cell lines and are associated with poor prognosis. Additionally, we observed differences in immune infiltration patterns based on the specific overexpressed gene. These findings suggest potential avenues for therapeutic intervention, such as the use of combination therapies with crizotinib, including immunotherapy or targeted therapies aimed at resistance pathways. These strategies could enhance treatment efficacy in tumors expressing these genes. ConclusionsSIRT2, TFEB, TM9SF4, CINH3, and ADRM1 are potential biomarkers for crizotinib-resistant and worse prognosis in LUAD. Our findings provide valuable insights into the mechanisms of crizotinib resistance and potential avenues for therapeutic intervention. HighlightsO_LIIn silico analysis identified nine overexpressed genes in crizotinib-resistant lung adenocarcinoma cell lines, all associated with worse prognosis. C_LIO_LITumor levels of SIRT2, TFEB, TM9SF4, CINH3, and ADRM1 correlate with higher infiltration of immunosuppressive populations and, the last three, with lower infiltration of immune-promoting cells. C_LIO_LIThese genes are potentially druggable targets in the context of crizotinib resistance, with existing treatments that could be explored. C_LIO_LIThe tumor microenvironment (TME) may play a significant role in these tumors, suggesting that immunotherapy could be a viable treatment option in this setting. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/662953v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@16075ecorg.highwire.dtl.DTLVardef@1de1942org.highwire.dtl.DTLVardef@4c60eaorg.highwire.dtl.DTLVardef@6ec6b4_HPS_FORMAT_FIGEXP M_FIG C_FIG