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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
Harnessing the FGFR2/NF2/YAP signaling-dependent necroptosis to develop an FGFR2/IL-8 dual blockade therapeutic
Dongshao Chen1,2, Zitong Zhao3, Ruoxi Hong2
1State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China.
Abstract:
The multifaceted roles and mechanisms of necroptosis in cancer cells remain incompletely understood. Here, we demonstrate that FGFR2 inhibition potently inhibits esophageal squamous cell carcinoma (ESCC) by inducing necroptosis in a RIP1/MLKL-dependent manner and show RIP3 is dispensable in this pathway. Notably, MST1 is identified as a necroptotic pathway component that interacts with RIP1 and MLKL to promote necroptosis by phosphorylating MLKL at Thr216. Additionally, FGFR2 inhibition induces Ser518 phosphorylation and triggers ubiquitin-mediated degradation of NF2, culminating in Hippo pathway suppression. Subsequently, YAP activation promotes RIP1 and MLKL transcriptional upregulation, further amplifying necroptosis. Intriguingly, IL-8 derived from necrotic cells stimulates peripheral surviving tumor cells to increase PD-L1 expression. Dual blockade of FGFR2/PD-L1 or FGFR2/IL-8-CXCR1/2 robustly impedes tumor growth in humanized mouse xenografts. Collectively, our findings delineate an alternative FGFR2-NF2-YAP signaling-dependent necroptotic pathway and shed light on the immunoregulatory role of FGFR2, offering promising avenues for combinatorial therapeutic strategies in clinical cancer management.
Insights
Fibroblast growth factor receptor 2 (FGFR2) inhibition triggers cancer cell death via necroptosis (programmed necrosis). This pathway involves MST1, NF2, and YAP, and also impacts immune responses, offering new therapeutic targets for esophageal squamous cell carcinoma.
Area of Science:
- Molecular Oncology
- Cell Death Pathways
- Cancer Immunology
Background:
- Necroptosis mechanisms in cancer are not fully elucidated.
- Esophageal squamous cell carcinoma (ESCC) requires novel therapeutic strategies.
- FGFR2 signaling is implicated in various cancers.
Purpose of the Study:
- To investigate the role of FGFR2 inhibition in ESCC.
- To elucidate the molecular mechanisms underlying FGFR2 inhibition-induced cell death.
- To explore the immunomodulatory effects and therapeutic potential in ESCC.
Main Methods:
- Inhibition of FGFR2 in ESCC cell lines and xenograft models.
- Analysis of necroptosis pathway components (RIP1, MLKL, RIP3, MST1).
- Investigation of Hippo pathway regulators (NF2, YAP) and downstream targets.
- Assessment of immune checkpoint ligand (PD-L1) expression and cytokine signaling (IL-8).
- Evaluation of combination therapies targeting FGFR2 and immune checkpoints.
Main Results:
- FGFR2 inhibition induces RIP1/MLKL-dependent necroptosis in ESCC, independent of RIP3.
- MST1 acts as a key mediator, phosphorylating MLKL.
- FGFR2 inhibition suppresses the Hippo pathway via NF2 degradation, activating YAP.
- YAP activation upregulates RIP1 and MLKL, amplifying necroptosis.
- Necrotic cells release IL-8, increasing PD-L1 expression in surviving tumor cells.
- Combined FGFR2 and PD-L1 or IL-8 pathway blockade significantly inhibits tumor growth.
Conclusions:
- FGFR2 inhibition triggers necroptosis through a novel NF2-YAP-dependent pathway in ESCC.
- FGFR2 plays an immunoregulatory role by influencing PD-L1 expression via IL-8.
- Dual blockade strategies targeting FGFR2 and immune pathways show significant therapeutic promise for ESCC.
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