Gastric cancer, the fifth most prevalent cancer globally, has the second-highest fatality rate due to limited treatment options. Advanced targeted treatments are crucial, especially for HER2-negative cases, accounting for 80-88% of patients. Currently, only one targeted drug is available for gastric cancer, benefiting less than 20% of patients, with less than 10% applicability in Taiwan. Dr. Wang's team aims to unravel gastric cancer progression mechanisms and identify new biomarkers, increasing the number of patients benefiting from targeted drug therapy to 40%.

This study found a significant association between poor clinical outcomes in HER2-negative gastric cancer and PHD finger protein 8 (PHF8, KDM7B). Reducing PHF8 levels substantially decreased cancer progression in gastric cancer cells and mouse xenografts. The primary cause of gastric cancer cell spread is the loss of function of tumor suppressor protein PTEN. The team discovered that two enzymes, PHF8 and PKCα, play key roles in cancer progression by analyzing big data from over 300 gastric cancer cases.

PHF8, abundant in gastric cancer tissue, promotes PKCα overproduction, leading to tumor suppressor failure. Notably, PHF8 interacts with c-Jun on the PRKCA promoter encoding PKCα. Inhibiting PHF8 or PKCα upregulates PTEN expression, which can be rescued by ectopic PKCα expression or an active Src, indicating PTEN destabilization occurs mainly via the PKCα-Src axis. The approved blood cancer drug, midostaurin, inhibits PKCα. The team applied midostaurin as a targeted therapy to zebrafish and mice with gastric cancer, proving its efficacy in shrinking tumors and inhibiting cancer spread. In conclusion, the PHF8/c-Jun-regulated PKCα-Src-PTEN pathway offers a potential prognostic and therapeutic target in HER2-negative advanced gastric cancer.