# GFPT2 drives sunitinib resistance of renal cell carcinoma via enzyme-dependent and -independent manners

## TL;DR

The enzyme GFPT2 contributes to resistance to the drug sunitinib in kidney cancer through both metabolic and non-metabolic pathways.

## Contribution

GFPT2 drives sunitinib resistance in renal cell carcinoma via two distinct mechanisms: O-GlcNAcylation-YAP1 and KEAP1-NRF2.

## Key findings

- Elevated glutamine levels and upregulated GFPT2 are linked to sunitinib resistance in RCC.
- GFPT2 modulates O-GlcNAcylation and YAP1 stability, reducing drug sensitivity.
- GFPT2 interacts with KEAP1 to suppress NRF2 degradation, promoting antioxidant gene transcription and resistance.

## Abstract

Intrinsic resistance to sunitinib in advanced renal cell carcinoma (RCC) remains a major barrier to improving patient survival outcomes. However, the molecular mechanisms driving this resistance remain incompletely elucidated. In this study, we first observed elevated glutamine levels in sunitinib-resistant RCC models; notably, glutamine deprivation substantially impaired the growth and proliferation of RCC cells. We further demonstrated that abnormal upregulation of GFPT2—a key enzyme in glutamine metabolism—was associated with reduced sunitinib sensitivity and enhanced drug resistance in RCC. Mechanistically, we uncovered that GFPT2 modulates cellular O-GlcNAcylation levels, which in turn enhances the stability and nuclear translocation of YAP1—ultimately contributing to reduced sunitinib sensitivity. In addition, we also identified an additional non-metabolic role of GFPT2: it directly interacts with the Kelch domain of KEAP1, thereby reducing NRF2 binding to this domain and suppressing NRF2 ubiquitination-dependent degradation. Consequently, this regulatory cascade dysregulates the transcription of downstream antioxidant genes (e.g., HMOX1 and NQO1), ultimately driving NRF2-dependent sunitinib resistance in RCC. Critically, this KEAP1-NRF2 axis-mediated mechanism operates independently of GFPT2's metabolic role in regulating O-GlcNAcylation. Collectively, our findings demonstrate that GFPT2 modulates sunitinib sensitivity and drives drug resistance in RCC via dual mechanisms: a metabolic pathway (O-GlcNAcylation-YAP1) and a non-metabolic pathway (KEAP1-NRF2). Targeting the non-metabolic functions of GFPT2 thus holds promise for enhancing sunitinib sensitivity in RCC while potentially mitigating treatment-related side effects.