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Harmine suppresses pancreatic cancer through DYRK1A-mediated hyper-activated RAS/MAPK inhibition
Cen Liu1, Jinchai Qi1, Danyang Ye1
1Beijing University of Chinese Medicine, Beijing 102400, China.
Biochemical Pharmacology
|August 31, 2025
Summary
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) regulates KRAS G12D in pancreatic cancer. Harmine inhibits DYRK1A, suppressing tumor growth and offering a new therapeutic target for KRAS G12D-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- KRAS G12D mutations are prevalent in pancreatic cancer (PC), driving tumor growth.
- Emerging KRAS G12D inhibitors show efficacy but face resistance, necessitating new therapeutic strategies.
- Identifying novel targets is crucial for overcoming resistance and improving PC treatment outcomes.
Purpose of the Study:
- To investigate the role of Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in regulating KRAS G12D activity in PC.
- To explore harmine (HM) as a potential therapeutic agent targeting DYRK1A in PC.
- To elucidate the molecular mechanisms underlying DYRK1A's modulation of the KRAS G12D/MAPK pathway.
Main Methods:
- Biochemical assays to assess DYRK1A's phosphatase activity and its effect on KRAS G12D-GTP levels.
- Fluorescence colocalization, bimolecular fluorescence complementation (Bi-FC), and co-immunoprecipitation (Co-IP) to confirm DYRK1A-KRAS G12D interaction.
- RNA sequencing to analyze gene expression changes induced by HM treatment.
- Caenorhabditis elegans models to validate DYRK1A as a therapeutic target.
Main Results:
- DYRK1A knockdown inhibited KRAS G12D hyperactivation, demonstrating its role in modulating KRAS G12D levels.
- Harmine (HM) was identified as an inhibitor of DYRK1A, leading to suppressed KRAS G12D/MAPK activity and reduced PC cell malignancy.
- Direct interaction between DYRK1A and KRAS G12D was confirmed, with DYRK1A's kinase activity essential for KRAS G12D activation.
- HM treatment downregulated RAS-related pathway genes and showed potential to inhibit autophagy in PC cells.
- Loss-of-function mutations in the DYRK1A homolog (mbk-1) in C. elegans suppressed KRAS G12D-induced phenotypes.
Conclusions:
- DYRK1A plays a critical role in activating KRAS G12D and promoting PC progression.
- Harmine suppresses the RAS/MAPK pathway by inhibiting DYRK1A kinase activity.
- DYRK1A represents a promising therapeutic target for KRAS G12D-driven pancreatic cancer.
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