by Sarah E. Glass
Treatment resistance is especially pronounced in gastric cancer and contributes to patient mortality, highlighting the need for resensitization strategies.
Robert Coffey, MD, Xiaodi Zhao, PhD, and colleagues compared the secretome, or secreted proteins, of chemoresistant and chemosensitive human gastric cancer cell lines to identify biomarkers of resistance. CGA, the alpha-subunit of glycoprotein hormones, was one of the top proteins secreted from chemoresistant lines. Moreover, CGA was increased in the plasma of patients undergoing chemotherapy, especially in those who did not respond to therapy or had poor survival.
CGA secretion, as well as its interaction with EGFR, was dependent upon its modification by glycosylation. EGFR activation by CGA led to upregulation of GATA2, a transcription factor, which could then increase levels of CGA, creating a positive feed-forward loop to amplify chemoresistance in gastric cancer.
This discovery, reported in The Journal of Clinical Investigation, could lead to combination therapies targeting CGA and EGFR to restore chemosensitivity in gastric cancer patients.
This research was supported by the National Natural Science Foundation of China, National Key R&D Program of China, China Association for Science and Technology, U.S. National Institutes of Health (grants CA197570, CA248505, CA236733, CA009582, TR002245), American Cancer Society, and Youth Innovation Promotion Association of the Chinese Academy of Sciences.
