This study identifies a key role of WDR4/PTPN23 axis in NSCLC progression by suppressing lysosomal degradation of EGFR and c-MET and suggests a previously unappreciated strategy for treating EGFR TKI-resistant NSCLC by reactivating the degradation of EGFR mutant and c-MET. The gene discussed is WDR4; the disease is non-small cell lung carcinoma.