P4HA2-mediated HIF-1α stabilization promotes erdafitinib-resistance in FGFR3-alteration bladder cancer
Xuexiang Li1, Yunxue Li1, Bing Liu1
1Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Erdafitinib is a novel fibroblast growth factor receptor (FGFR) inhibitor that has shown great therapeutic promise for solid tumor patients with FGFR3 alterations, especially in urothelial carcinoma. However, the mechanisms of resistance to FGFR inhibitors remain poorly understood. In this study, we found Erdafitinib could kill cells by inducing incomplete autophagy and increasing intracellular reactive oxygen species levels. We have established an Erdafitinib-resistant cell line, RT-112-RS. whole transcriptome RNA sequencing (RNA-Seq) and Cytospace analysis performed on Erdafitinib-resistant RT-112-RS cells and parental RT-112 cells introduced P4HA2 as a linchpin to Erdafitinib resistance. The gain and loss of function study provided evidence for P4HA2 conferring such resistance in RT-112 cells. Furthermore, P4HA2 could stabilize the HIF-1α protein which then activated downstream target genes to reduce reactive oxygen species levels in bladder cancer. In turn, HIF-1α could directly bind to P4HA2 promoter, indicating a positive loop between P4HA2 and HIF-1α in bladder cancer. These results suggest a substantial role of P4HA2 in mediating acquired resistance to Erdafitinib and provide a potential target for bladder cancer treatment.
Insights
Acquired resistance to Erdafitinib, an FGFR inhibitor, in bladder cancer involves P4HA2. This protein stabilizes HIF-1α, creating a feedback loop that reduces reactive oxygen species and promotes Erdafitinib resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Erdafitinib is a promising fibroblast growth factor receptor (FGFR) inhibitor for solid tumors with FGFR3 alterations, particularly urothelial carcinoma.
- Mechanisms underlying resistance to FGFR inhibitors like Erdafitinib are not well understood.
- Erdafitinib induces cell death via incomplete autophagy and increased reactive oxygen species (ROS).
Purpose of the Study:
- To investigate the molecular mechanisms of acquired resistance to Erdafitinib in bladder cancer.
- To identify key proteins involved in mediating resistance to Erdafitinib treatment.
- To explore potential therapeutic targets for overcoming Erdafitinib resistance.
Main Methods:
- Establishment of an Erdafitinib-resistant cell line (RT-112-RS) from parental RT-112 cells.
- Whole transcriptome RNA sequencing (RNA-Seq) and Cytospace analysis to compare resistant and parental cells.
- Gain- and loss-of-function studies to assess the role of identified proteins in resistance.
Main Results:
- P4HA2 was identified as a key mediator of Erdafitinib resistance in RT-112 cells.
- P4HA2 stabilizes HIF-1α protein, which activates downstream genes to decrease ROS levels.
- A positive feedback loop was observed where HIF-1α binds to the P4HA2 promoter, enhancing its expression.
Conclusions:
- P4HA2 plays a significant role in acquired resistance to Erdafitinib in bladder cancer.
- The P4HA2-HIF-1α axis represents a potential therapeutic target for overcoming Erdafitinib resistance.
- Understanding this resistance mechanism could lead to improved treatment strategies for bladder cancer patients.
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