Calcium triggers calmodulin degradation to induce EGF receptor instability and overcome non-small cell lung cancer resistance to tyrosine kinase inhibitors.

Epidermal growth factor receptor (EGFR)-targeted therapy by tyrosine kinase inhibitors (TKIs) is the first-line treatment of non-small cell lung cancer (NSCLC). However, EGFR mutation-mediated TKIs resistance remains a major hurdle for NSCLC treatment. This study found the opposite roles of calcium (Ca) and its receptor calmodulin (CaM) in regulating EGFR protein stability. Elevated Ca facilitates degradation of EGFR TKI-resistant mutant proteins, whereas CaM protects them from degradation. Mechanistically, Ca binding to CaM triggers heat shock protein 70-mediated lysosomal degradation of CaM protein, resulting in reduced CaM binding to EGFR, thereby facilitating EGFR proteasomal degradation mediated by the E3 ubiquitin ligase FBXL2. Notably, a combination of Ca activator curcumin, FBXL2 activator nebivolol, and osimertinib significantly inhibits EGFR-driven TKI-resistant NSCLC growth. Together, this study highlights the importance of the negative feedback loop between Ca and CaM and the critical regulatory role of Ca/CaM in the FBXL2-mediated EGFR degradation, providing a viable therapeutic strategy for TKI-resistant NSCLC.