In summary, our results highlight the critical role of Ca2+/CaM in regulation of FBXL2-mediated EGFR instability and reveal that targeting Ca2+ by curcumin is a potential therapeutic strategy for the treatment of EGFR-driven disorders, such like EGFR-TKI–resistant NSCLC. The gene discussed is EGFR; the disease is non-small cell lung carcinoma.