Jeong-Ki Min et al. found loss of Dsg2 promoted gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation, a non-receptor tyrosine kinase (nRTK), by which increased p-AKT and p-ERK were involved, indicating PI3K and MAPK pathways were activated. Here, DSG2 is linked to gallbladder carcinoma.