Professor Dong Zigang's research team at Zhengzhou University (ZZU) has published two major studies in Nature Communications and PNAS, shedding light on the molecular mechanisms driving chemotherapy resistance in esophageal squamous cell carcinoma (ESCC) and gastric cancer. The findings offer new biomarkers and therapeutic targets for precision oncology.
Neoadjuvant chemotherapy is widely used to improve survival in ESCC, lung, and breast cancers. However, 50-70 percent of patients do not respond, suffering toxic side effects without benefit. The team discovered that INCENP and CDCA8 are highly expressed in non-responsive ESCC, lung, and breast cancer tissues and correlate with poor prognosis. Mechanistically, METTL3-mediated m6A modification of INCENP and CDCA8 enhances their translation via YTHDF3, promoting resistance to paclitaxel and cisplatin. Inhibiting these genes re-sensitized tumors to chemotherapy, presenting promising therapeutic targets.
For gastric cancer, the team discovered that the serine metabolism enzyme PHGDH is upregulated and activated by kinase WNK1 through phosphorylation at Ser349 and Ser371. This drives metabolic reprogramming, boosts antioxidant defense and DNA repair, and reduces sensitivity to oxaliplatin. PHGDH phosphorylation levels and serine metabolic activity correlate with treatment response, serving as dual biomarkers for metabolic vulnerability and chemotherapy responsiveness.
Both studies, conducted in collaboration with the China-US (Henan) Hormel Cancer Institute and Tianjian Laboratory of Advanced Biomedical Sciences, advance our understanding of chemotherapy resistance and open new avenues for personalized cancer therapy.
Upregulation of INCENP and CDCA8 contributes to poor NACT response. [Photo/zzu.edu.cn]
Upregulation of INCENP and CDCA8 contributes to poor NACT response. [Photo/zzu.edu.cn]