In this study, we found a negative feedback loop between Ca2+ and CaM and the critical role of Ca2+/CaM in regulation of FBXL2-mediated EGFR degradation, suggesting that targeting the Ca2+/CaM/FBXL2/EGFR axis may be a potential novel therapeutic strategy for the treatment of EGFR-TKI–resistant NSCLC. Here, EGFR is linked to non-small cell lung carcinoma.