Deciphering Landscape of Driver Transcription Factors in Large Cell Neuroendocrine Carcinoma (LCNEC) of the Lungs Through a Novel Bioinformatics Approach

<bold>Background:</bold> LCNEC, a severe lung cancer with poor outcomes, lacks effective treatments. The critical role of transcription factors (TFs) in its development highlights the need for advanced therapies. Traditional research methods, focusing solely on TF expression, overlook the complex regulatory and post-translational modifications essential for TF function. <bold>Aims:</bold> Create a bioinformatics method to find TFs with changed activity in LCNEC. Find key TFs in LCNEC development, focusing on transcription and translation roles. Investigate these TFs as LCNEC treatment targets. <bold>Methods:</bold> We used a novel bioinformatics approach to spot TF activity differences in LCNEC by comparing TF target gene expression in tumor vs. healthy tissues. This identifies TFs with significant activity shifts, regardless of protein levels, through three statistical analyses. <bold>Results:</bold> Our method showed TP53 commonly suppressed in LCNEC, consistent with its cancer role. We identified MYC, active in 94% of LCNEC cases, essential for cell division, and ZEB1, associated with metastasis via EMT. Resource constraints limited experimental validation to MYC and ZEB1. Immunohistochemistry indicated MYC's increased activity in LCNEC stems from post-translational modifications, not overexpression, challenging traditional views and emphasizing these modifications' role in cancer. <bold>Conclusion:</bold> This research enhances our understanding of TF regulation in LCNEC, emphasizing the importance of TFs such as MYC and ZEB1. Our bioinformatics method surpasses prior research constraints, providing deeper insight into TF activity in cancer and new paths for LCNEC therapies.