Despite developing a significant correlation index based on the overexpressed MEOX2-GLI1 axis, our results depict a novel transcriptional and likely epigenetic mechanism involved in lung tumor biology and cancer drug resistance mechanisms to platinum-based and/or target EGFR-TKI-based therapy responses, affecting lung tumor cell viability, cellular migration/proliferation, clinical prognosis and overall survival in lung cancer patients. The gene discussed is EGFR; the disease is lung carcinoma.