2025-09-22 デューク大学
<関連情報>
- https://pratt.duke.edu/news/using-iron-to-destroy-multiple-myeloma-cancer-cells/
- https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2025029950/547268/Targeting-STK17B-kinase-activates-ferroptosis-and?redirectedFrom=fulltext
STK17Bキナーゼを標的とすることでフェロプトーシスを活性化し、多発性骨髄腫における薬剤耐性を抑制する Targeting STK17B kinase activates ferroptosis and suppresses drug resistance in multiple myeloma
Zhibo Yan,Zhannan Han,Yihui Wang,Maja Beus,Yu Zhang,Alfredo Picado,Carrow I. Wells,Jian Wu,Loren B. Weidenhammer,Karla M. Pires,Elizabeth A. Leibold,Liang Liu,David M. Gooden,Ivan Spasojevic,Erik Soderblom,Yubin Kang,Lawrence H Boise,Timothy M. Willson,Mikhail A. Nikiforov
Blood Published:September 12, 2025
DOI:https://doi.org/10.1182/blood.2025029950
Key Points
- STK17B phosphorylates key regulators of iron homeostasis, thereby controlling an equilibrium between pro- and anti-ferroptotic proteins.
- Pharmacological inhibition of STK17B activates ferroptosis, alleviates MM drug resistance and suppresses tumor burden in MM mouse models.
The progression of multiple myeloma (MM), an incurable malignancy of plasma cells, is often associated with the suppression of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. The mechanisms underlying this suppression remain largely unknown. Here, we identified STK17B kinase as a critical suppressor of ferroptosis in MM. Elevated levels of STK17B are associated with poor overall survival in MM patients and STK17B expression is significantly higher in relapsed vs newly diagnosed MM cases. We found that inhibiting STK17B in MM cells increased the labile iron pool, enhanced lipid peroxidation, and sensitized cells to conventional anti-MM therapies. Notably, an orally available, in-house-generated STK17B inhibitor induced ferroptosis and significantly reduced tumor growth in MM xenograft mouse models. Mechanistically, proximity labeling assay combined with the phospho-proteomic analysis identified two major regulators of iron uptake and transport as direct targets of STK17B: iron-responsive element binding protein 2 (IREB2) and heat shock protein family B member 1 (HSPB1). We demonstrated that STK17B phosphorylates critical regulatory sites on IREB2 (S157) and HSPB1 (S15), thereby modulating the balance between IREB2 and HSPB1 downstream effectors, pro-ferropototic transferrin receptor and anti-ferroptotic ferritin heavy chain proteins. Furthermore, we demonstrated that STK17B indirectly maintains activating phosphorylation of STAT3, a ferroptosis suppressor and a major driver of MM pathobiology. Our findings uncovered a clinically relevant and targetable STK17B-pIREB2S157/pHSPB1S15 signaling axis that suppresses ferroptosis and contributes to drug resistance in MM.
