2026-10-28 東邦大学
図1．DYRK2阻害によるSMO阻害薬耐性の克服モデル
＜関連情報＞
- https://www.toho-u.ac.jp/press/2026_index/20261028-1666.html
- https://febs.onlinelibrary.wiley.com/doi/10.1002/1873-3468.70484
DYRK2阻害は、ヘッジホッグ駆動型腫瘍におけるSMO阻害剤耐性を克服する DYRK2 inhibition overcomes resistance to SMO inhibitors in Hedgehog-driven tumors
Sae Tomura, Akira Kawamura, Sora Suzuki, Kohji Yamada, Yuto Sumida, Takamitsu Hosoya, Isao Kii, Kiyotsugu Yoshida, Saishu Yoshida
FEBS Letters Published: 27 October 2026
DOI:https://doi.org/10.1002/1873-3468.70484
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 SMOW535L mutation. Genetic depletion and pharmacological inhibition of DYRK2 suppressed Hh target gene expression in SMOW535L-expressing cells. In contrast to vismodegib, DYRK2 inhibition reduced oncosphere formation in SMOW535L-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.
