In a groundbreaking study poised to reshape therapeutic strategies for multiple myeloma, researchers at Duke University have identified a pivotal enzyme that governs iron regulation within cancer cells, revealing a novel vulnerability by reactivating a suppressed cell death pathway. This discovery, detailed in the prestigious journal Blood, highlights how inhibiting the kinase STK17B unlocks the potential of ferroptosis—a unique form of programmed cell death dependent on iron-mediated oxidative damage—thereby not only eliminating malignant plasma cells but also enhancing the efficacy of existing treatments.
Multiple myeloma (MM) stands as one of the most challenging hematologic malignancies, characterized by the unchecked proliferation of neoplastic plasma cells within the bone marrow. These malignant cells disrupt normal hematopoiesis and produce aberrant antibodies, collectively contributing to severe immunodeficiency, organ dysfunction, and debilitating bone lesions. Despite advances in targeted therapies, MM remains incurable, owing largely to the emergence of drug resistance and frequent relapse, mechanisms that remain poorly understood at the molecular level.
Intriguingly, prior observations established a correlation between MM and the suppression of ferroptosis, a non-apoptotic form of cell death that is triggered by iron-induced lipid peroxidation leading to irreversible damage of the cellular membrane. Under physiological conditions, ferroptosis acts as a crucial homeostatic regulator of cell viability, preventing the survival of cells with excessive iron load. However, in MM cells, this safeguard is aberrantly disabled, allowing these cancerous cells to accumulate iron at toxic levels without succumbing to cell death, thereby sustaining their malignancy.
Professor Mikhail Nikiforov and his interdisciplinary team have elucidated that the kinase STK17B functions as a central modulator safeguarding MM cells from ferroptotic death. STK17B, traditionally recognized for its roles in apoptosis regulation and T-cell activation, was found to intricately balance pro- and anti-ferroptotic proteins, fortifying the cancer cells against iron-induced oxidative stress. The enzyme’s upregulation correlates strongly with poorer survival outcomes in MM patients, particularly those facing relapsed or refractory disease, underscoring its critical function in mediating resistance to therapy.
Capitalizing on this molecular insight, the team employed a novel inhibitor designed by medicinal chemists led by Timothy Willson from the UNC Eshelman School of Pharmacy to target STK17B’s regulatory role over iron metabolism in MM cells. Remarkably, inhibition of STK17B reinstated ferroptosis by promoting iron overload and enhancing lipid peroxidation within the malignant plasma cells. Beyond merely inducing cell death, the STK17B inhibitor sensitized these cells to conventional chemotherapeutic agents, suggesting a potent combinatorial approach to overcome drug resistance.
To validate their findings in vivo, researchers utilized mouse models engrafted with human MM cells and administered the orally bioavailable STK17B inhibitor. The compound demonstrated robust antitumor activity, significantly curtailing tumor growth by reactivating ferroptosis pathways. This preclinical success offers a compelling proof of concept that pharmacological targeting of iron homeostasis regulators can dismantle the cancer’s protective shield and amplify the impact of existing therapeutic regimens.
This innovative therapeutic avenue does not merely address the issue of cell death resistance but also taps into the broader cellular iron metabolism that cancer cells exploit for survival and proliferation. By dismantling the enhanced iron buffering systems through STK17B suppression, the treatment strategy fundamentally disrupts the pathological iron equilibrium, leading to lethal oxidative stress within the malignant cells.
Furthermore, the research team has advanced their discovery beyond the laboratory by filing a provisional patent, setting the stage for future clinical development and potential commercialization of STK17B-targeting agents. Their vision extends to exploring the applicability of this approach across other malignancies known for ferroptosis resistance, reflecting a transformative potential that transcends multiple myeloma alone.
This study is supported by significant funding from the National Institutes of Health and other prominent foundations, affirming the scientific and clinical relevance of the findings. Collaborative efforts have integrated expertise from structural genomics, pharmacology, oncology, and bioengineering, exemplifying the multidisciplinary nature of cutting-edge cancer research in the modern era.
The implications of reactivating ferroptosis as a cancer treatment modality could herald a paradigm shift in tackling diseases marked by recalcitrant drug resistance. By unveiling the underappreciated role of STK17B in ferroptotic suppression, the researchers have unlocked new molecular targets that could redefine therapeutic strategies, making previously refractory cancers more vulnerable.
Duke University’s pioneering work offers hope for millions affected by multiple myeloma, signaling a future where manipulating cellular iron metabolism and ferroptosis may become central in cancer therapy. The continued pursuit of refining the STK17B inhibitor and extending investigations into combination treatments marks an exciting frontier in hematologic oncology and personalized medicine.
As the research progresses, it stands as a testament to the power of understanding intricate cellular death pathways and the development of precision inhibitors to overcome longstanding challenges in cancer treatment. This milestone discovery not only provides mechanistic insights but also lays a practical foundation for the next generation of anti-myeloma drugs poised to improve patient outcomes profoundly.
Subject of Research: Cells
Article Title: Targeting STK17B kinase activates ferroptosis and suppresses drug resistance in multiple myeloma
News Publication Date: 12-Sep-2025
Web References: https://doi.org/10.1182/blood.2025029950
References: Yan, Z., Han, Z., Beus, M., Zhang, Y., Picado, A., Wells, C., Wu, J., Weidenhammer, L., Pires, K., Leibold, E., Liu, L., Gooden, D., Spasojevic, I., Soderblom, E., Kang, Y., Boise, L., Willson, T., Nikiforov, M. (2025). Targeting STK17B kinase activates ferroptosis and suppresses drug resistance in multiple myeloma. Blood. DOI: 10.1182/blood.2025029950
Image Credits: Duke University
Keywords: Health and medicine, Cancer, Multiple myeloma, Blood cancer, Clinical medicine, Biomedical engineering
