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

Background

Lung 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.

Methods

An 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.

Results

We 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.

Conclusions

SIRT2, 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.

Highlights

• In silico analysis identified nine overexpressed genes in crizotinib-resistant lung adenocarcinoma cell lines, all associated with worse prognosis.

• Tumor 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.

• These genes are potentially druggable targets in the context of crizotinib resistance, with existing treatments that could be explored.

• The tumor microenvironment (TME) may play a significant role in these tumors, suggesting that immunotherapy could be a viable treatment option in this setting.

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