De novo and acquired resistance are major impediments to the efficacy of conventional and targeted
cancer therapy. In unselected
gastric cancer (GC) patients with advanced disease, trials combining
chemotherapy and an anti-EGFR
monoclonal antibody have been largely unsuccessful. In an effort to identify
biomarkers of resistance so as to better select patients for such trials, we screened the secretome of
chemotherapy-treated human GC cell lines. We found that levels of CGA, the α-subunit of
glycoprotein hormones, were markedly increased in the
conditioned media of chemoresistant GC cells, and CGA immunoreactivity was enhanced in GC tissues that progressed on
chemotherapy. CGA levels in plasma increased in GC patients who received
chemotherapy, and this increase was correlated with reduced responsiveness to
chemotherapy and poor survival. Mechanistically, secreted CGA was found to bind to EGFR and activate EGFR signaling, thereby conferring a survival advantage to GC cells. N-glycosylation of CGA at Asn52 and Asn78 is required for its stability, secretion, and interaction with EGFR. GATA2 was found to activate CGA transcription, whose increase, in turn, induced the expression and phosphorylation of GATA2 in an EGFR-dependent manner, forming a positive feedback circuit that was initiated by GATA2 autoregulation upon sublethal exposure to
chemotherapy. Based on this circuit, combination strategies involving anti-EGFR
therapies or targeting CGA with
microRNAs (miR-708-3p and miR-761) restored
chemotherapy sensitivity. These findings identify a clinically actionable CGA/EGFR/GATA2 circuit and highlight CGA as a predictive
biomarker and therapeutic target in chemoresistant GC.