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(2+)) and its receptor calmodulin (CaM) in regulating EGFR protein stability. Elevated Ca(2+) facilitates degradation of EGFR TKI-resistant mutant proteins, whereas CaM protects them from degradation. Mechanistically, Ca(2+) 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(2+) activator curcumin, FBXL2 activator nebivolol, and osimertinib significantly inhibits EGFR(T790M/C797S)-driven TKI-resistant NSCLC growth. Together, this study highlights the importance of the negative feedback loop between Ca(2+) and CaM and the critical regulatory role of Ca(2+)/CaM in the FBXL2-mediated EGFR degradation, providing a viable therapeutic strategy for TKI-resistant NSCLC.