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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

Abstract:

KRAS ^G12D is the most frequent RAS mutation in pancreatic cancer (PC). Recently, small molecule inhibitors like MRTX1133, which target KRAS ^G12D, have shown efficacy in inhibiting PC growth. However, the development of intrinsic and acquired resistance to these inhibitors has been observed, necessitating the identification of novel therapeutic targets. In this study, we first reported that dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) could modulate the level of KRAS ^G12D-GTP depending on its phosphatase activity, and its knockdown could inhibit the hyperactivation of KRAS ^G12D. It was found that DYRK1A could be the target of harmine (HM) to regulate the activity of KRAS ^G12D/MAPK, resulting in HM inhibiting the malignant phenotypes of PC cells. To elucidate the underlying mechanism, we confirmed the interaction between DYRK1A and KRAS ^G12D using fluorescence colocalization, bimolecular fluorescence complementation (Bi-FC), and co-immunoprecipitation (Co-IP). We further established that the kinase activity was essential for DYRK1A to activate KRAS ^G12D. In addition, RNA sequencing revealed that HM induced downregulation of RAS-related pathway gene expression in PC. It was also found that HM may demonstrate anti-PC effect by inhibiting autophagy. In spite of the mechanism, we further validated the potential of DYRK1A as a therapeutic target for KRAS ^G12D-induced cancer based on Caenorhabditis elegans model. The loss-of-function mutation in mbk-1 (DYRK1A homologous gene) could inhibit the multivulva (Muv) phenotype in nematodes with KRAS ^G12D. Collectively, our findings indicate that HM could suppress the RAS/MAPK pathway by inhibiting DYRK1A kinase activity, suggesting that DYRK1A could serve as a therapeutic target for PC treatment.

Insights

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.

Read full analysis

Keywords:

DYRK1A Harmine Pancreatic cancer RAS mutation

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