✓ CD44 and SSP1 methylation are prognostic factors in LUAD patients.✓ SPP1 methylation modulates its expression and is related to 1st and 2nd EGFR-TKI resistance of NSCLC.✓ CD44-SSP1 axis is implicated in the trasformation of ADC in SCLC under EGFR-TKI selettive pressure. This evidence concerns the gene EGFR and small cell lung carcinoma.