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Selenium Nanoparticles Selectively Target KRAS G13D to Inhibit Colorectal Cancer
Xiaoting Liu1,2, Chong Wu2, Shiyao Song3
1Department of Gastrointestinal Surgery, School of Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China.
Abstract:
Despite substantial progress in KRAS-targeted therapies, specific inhibitors of the KRAS G13D mutant remain unavailable. In a retrospective analysis, we found a notable downregulation of glutathione peroxidase 2 (GPX2) in KRAS G13D- mutant colorectal cancer (CRC), which correlated with poor outcomes. We hypothesized that GPX2 acts as a tumor suppressor and that its restoration could render KRAS G13D-driven tumors vulnerable. In this study, we developed a selenium nanoparticle (SeNPs)-based nanostrategy to suppress KRAS G13D-driven tumors by modulating GPX2 expression. SeNPs upregulated GPX2 expression, thereby inhibiting metastasis through the GPX2-HIF1α-VEGF axis. Moreover, SeNPs release selenite (SeO3 2-) in situ, which interacts with the mutant pocket (residues 13-17) of the KRAS G13D protein. In vivo, this multimodal strategy demonstrated exceptional efficacy. In orthotopic CRC models, SeNPs significantly inhibited primary tumor growth and effectively prevented liver metastasis. In cell‑derived xenograft (CDX) and patient-derived xenograft (PDX) models, SeNPs achieved tumor inhibition rates of 70% and 61%, respectively. Collectively, this study demonstrates the first-in-class therapeutic potential of SeNPs against this recalcitrant KRAS mutant and provides a novel nanoplatform for KRAS G13D-targeted therapy.
Insights
Selenium nanoparticles (SeNPs) offer a novel therapy for KRAS G13D-mutant colorectal cancer (CRC) by restoring tumor suppressor GPX2. This approach inhibits tumor growth and metastasis, addressing an unmet clinical need.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- KRAS G13D-mutant colorectal cancer (CRC) lacks specific targeted therapies.
- Glutathione peroxidase 2 (GPX2) is downregulated in KRAS G13D CRC, correlating with poor prognosis.
- GPX2 restoration is hypothesized to sensitize KRAS G13D tumors to therapy.
Purpose of the Study:
- To develop a selenium nanoparticle (SeNPs)-based nanostrategy targeting KRAS G13D-driven tumors.
- To investigate the therapeutic potential of SeNPs by modulating GPX2 expression and inhibiting tumor progression.
Main Methods:
- Development of SeNPs for modulating GPX2 expression and delivering selenite.
- In vitro and in vivo studies using colorectal cancer cell lines and xenograft models (orthotopic, CDX, PDX).
- Analysis of GPX2-HIF1α-VEGF axis and KRAS G13D protein interaction.
Main Results:
- SeNPs successfully upregulated GPX2 expression, inhibiting metastasis via the GPX2-HIF1α-VEGF pathway.
- In situ released selenite interacted with the KRAS G13D mutant pocket.
- Significant inhibition of primary tumor growth and liver metastasis in orthotopic models.
- Tumor inhibition rates of 70% in CDX and 61% in PDX models.
Conclusions:
- SeNPs demonstrate first-in-class therapeutic potential against KRAS G13D-mutant CRC.
- This nanoplatform offers a novel strategy for targeting this recalcitrant cancer mutation.
- The study highlights SeNPs as a promising nanomedicine for precision oncology.
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