DYRK2 inhibition overcomes resistance to SMO inhibitors in Hedgehog‐driven tumors

Hedgehog (Hh) signaling is frequently activated in cancers, such as basal cell carcinoma and medulloblastoma. Although Smoothened (SMO) inhibitors such as vismodegib and sonidegib are used to treat Hh‐driven tumors, their efficacy is often limited by drug‐resistant SMO mutations. Here, we investigated whether targeting DYRK2, a positive regulator of Hh signaling downstream of SMO, suppresses Hh signaling driven by the drug‐resistant SMO W535L mutation. Genetic depletion and pharmacological inhibition of DYRK2 suppressed Hh target gene expression in SMO W535L ‐expressing cells. In contrast to vismodegib, DYRK2 inhibition reduced oncosphere formation in SMO W535L ‐expressing medulloblastoma cells. These findings identify DYRK2 as a regulatory node downstream of SMO and demonstrate that targeting DYRK2 represents a strategy to overcome resistance to SMO inhibitors in Hh‐driven tumors.

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Publication Details

Journal
FEBS Letters
Published
2026-10-27
DOI
https://doi.org/10.1002/1873-3468.70484
Primary Topic
Hedgehog Signaling Pathway Studies
Type
article
Field-Weighted Citation Impact
0.00

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article

DYRK2 inhibition overcomes resistance to SMO inhibitors in Hedgehog‐driven tumors

Akira Kawamura, Isao Kii, Kiyotsugu Yoshida, Kohji Yamada et al.
FEBS Letters
Hedgehog Signaling Pathway Studies
article

DYRK2 inhibition overcomes resistance to SMO inhibitors in Hedgehog‐driven tumors

Akira Kawamura, Isao Kii, Kiyotsugu Yoshida, Kohji Yamada, Takamitsu Hosoya, Saishu Yoshida, Yuto Sumida, Sora Suzuki, Sae Tomura
article en

Abstract

Hedgehog (Hh) signaling is frequently activated in cancers, such as basal cell carcinoma and medulloblastoma. Although Smoothened (SMO) inhibitors such as vismodegib and sonidegib are used to treat Hh‐driven tumors, their efficacy is often limited by drug‐resistant SMO mutations. Here, we investigated whether targeting DYRK2, a positive regulator of Hh signaling downstream of SMO, suppresses Hh signaling driven by the drug‐resistant SMO W535L mutation. Genetic depletion and pharmacological inhibition of DYRK2 suppressed Hh target gene expression in SMO W535L ‐expressing cells. In contrast to vismodegib, DYRK2 inhibition reduced oncosphere formation in SMO W535L ‐expressing medulloblastoma cells. These findings identify DYRK2 as a regulatory node downstream of SMO and demonstrate that targeting DYRK2 represents a strategy to overcome resistance to SMO inhibitors in Hh‐driven tumors.

FEBS Letters
Jikei University School of Medicine (JP), Toho University (JP), Shinshu University (JP), Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo (JP)
Yamada Science Foundation, Takeda Science Foundation, Takahashi Industrial and Economic Research Foundation, Japan Agency for Medical Research and Development, Kawano Masanori Memorial Public Interest Incorporated Foundation, SGH Foundation, Hokuto Foundation for Bioscience, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Jikei University School of Medicine, NOVARTIS Foundation (Japan) for the Promotion of Science, Chugai Pharmaceutical, Japan Society for the Promotion of Science
Good health and well-being
Openalex Percentile: Top 22%
Hedgehog Signaling Pathway Studies
DOIOpen Access PDFOpenAlex
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