Downregulation of GFPT2 enhances cisplatin chemotherapy sensitivity in STK11/KRAS mutant non-small cell lung cancer by regulating the hexosamine biosynthesis pathway, resisting tumor growth

Objective: To explore the role of GFPT2 in the sensitivity of STK11/KRAS lung Cancer cells to cisplatin chemotherapy, and its underlying mechanism.

Materials & methods: A549 and H460 cells were used to analyze the effect of GFPT2 on cisplatin chemotherapy sensitivity, as both carry KRAS mutations and H460 has LKB1 inactivation mutations, meeting the requirements of a KRAS/LKB1 co mutant tumor model. The levels of UDP-GlcNAc, OGT, OGA, and O-GlcNAc in the HBP pathway were also determined. To verify the potential role of HBP, we added OGT inhibitors. In vivo, we constructed a nude mouse model bearing A549 tumor to further validate the results of in vitro cell experiments.

Results: GFPT2 silencing can significantly inhibit cell proliferation, invasion, and migration, promote cell Apoptosis, and enhance the effect of cisplatin (p < 0.05). After OSMI-1 processing, GFPT2 enhances O-GlcNAc modification levels via the OGT-mediated HBP, thereby decreasing the sensitivity of STK11/KRAS mutant cells to cisplatin chemotherapy. In addition, GFPT2 silencing enhances the chemotherapy sensitivity of cisplatin and inhibits tumor growth, while overexpression of GFPT2 weakens this effect (p < 0.05). The above results provide new targets and combination therapy options for the clinical treatment of KRAS/LKB1 mutant lung Cancer.

Conclusion: Our study found that inhibiting GFPT2 can enhance the chemotherapy sensitivity of cisplatin to STK11/KRAS/LKB1 mutant NSCLCs cells through the OGT mediated HBP pathway, filling a key gap in the chemotherapy resistance mechanism of KRAS/LKB1 mutant lung Cancer.

Chemotherapy sensitivity; GFPT2; Hexosamine biosynthesis pathway; Lung cancer; STK11/KRAS co-mutation.