In this study, we identify dysregulation of calcineurin expression (by the mean of PPP3CB overexpression) as a critical node for activation of the KSR2/ERK pathway by EGFR TKI, and demonstrate that activation of this pathway is a mechanism of acquired resistance of EGFR-mutant NSCLC cells to EGFR TKI. This evidence concerns the gene EGFR and non-small cell lung carcinoma.