https://orcid.org/0000-0002-5198-0796
In this issue of Blood, Yan et al1 identified that STK17B was highly expressed in multiple myeloma (MM) cells from relapsed and drug-resistant patients with MM. Targeting STK17B suppressed MM growth and overcame drug resistance by the activation of ferroptosis. This study offers new insights into the relationship between STK17B and ferroptosis, as well as emerging therapeutic synergies.
MM is a hematological cancer of plasma cells. Despite advances in treatment modalities, the majority of patients relapse. The development of multidrug resistance is still an obstacle to the treatment of MM. Therefore, identifying targets for the development of novel therapeutics is a major challenge. The pathogenesis of MM is closely linked to dysregulated unfolded protein response due to the heightened production of immunoglobulin and the metabolic demands of uncontrolled malignant proliferation, which has prompted investigations into novel cell death mechanisms and their regulatory pathways.
Ferroptosis is an iron-dependent, distinct type of programmed cell death. Unlike apoptosis, ferroptosis does not involve features such as chromatin condensation or apoptotic body formation. Instead, ferroptotic cells show mitochondrial shrinkage, reduced cristae, and increased membrane density. Multiple metabolic pathways govern the activation of ferroptosis. These include glutathione peroxidase 4 (GPX4)–dependent and GPX4-independent pathways, as well as iron and lipid metabolism pathways.2 The MM microenvironment creates both opportunities and challenges for ferroptosis induction. MM cells maintain high protein synthesis. This creates elevated oxidative stress, which may make them vulnerable to further redox imbalance. Several MM treatment agents engage ferroptosis pathways. For example, bortezomib, a proteasome inhibitor, promotes ferroptosis in MM cells. It increases intracellular free Fe2+ levels through ferritin degradation. The combination of bortezomib with the GPX4 inhibitor (RSL-3) synergistically suppresses MM-cell growth by enhancing ferroptosis.3 In addition, many ferroptosis-related genes are predictive of clinical outcomes of various cancers.4 Modulating ferroptosis-driven pathways could help develop new targeted therapies for the treatment MM.5
Serine/threonine kinase 17B (STK17B), also known as death-associated apoptosis–inducing protein kinase 2, is a member of the death-associated protein kinase family and a regulator of apoptosis and autophagy. STK17B is highly expressed in lymphocytes. T cells from STK17B-deficient mice have a lower threshold for activation in response to T-cell receptor stimulation.6 A recent study found that targeting STK17B with inhouse-developed inhibitors enhanced T-cell activation. This also promoted antitumor immunity when given in combination with anti–PD-L1 therapy in a sarcoma model. These findings suggest STK17B plays an important role in immune modulation.7 Beyond its immunological functions, STK17B plays context-dependent roles in various cancers. In ovarian cancer, STK17B is highly expressed in tumors compared to normal counterparts. Deleting STK17B from ovarian cancer cells decreases tumor proliferation, invasion, and migration in vitro. It also suppresses the tumor growth in vivo.8 Conversely, the low STK17B expression is correlated with shorter survival in melanoma. The STK17B expression level is also positively associated with immune cell infiltration in the tumor microenvironment.9 The direct role of STK17B in activating ferroptosis in MM remains unclear.
To our knowledge, Yan et al identified that STK17B is a critical suppressor of ferroptosis in MM, for the first time. STK17B is highly expressed in relapsed MM and bortezomib nonresponders. Deletion of STK17B suppresses both drug-sensitive and drug-resistant MM-cell proliferation and induces ferroptosis, as evidenced by elevated levels of lipid peroxidation, increased levels of labile iron, and decreased levels of GPX4. Importantly, the authors generated a selective STK17B inhibitor, which significantly reduced tumor growth in MM xenograft mouse models. The inhibitor treatment was well tolerated in the mice. Intriguingly, using proximity labeling assay combined with the phosphoproteomic approaches, Yan et al identified that STK17B directly phosphorylated 2 major regulators of iron uptake and transport, iron-responsive element binding protein 2 (IREB2) and heat shock protein family B member 1 (HSPB1), controlling the balance between proferroptotic transferrin receptor and antiferroptotic ferritin heavy chain proteins.1 This study expands on the current understanding of how STK17B regulates ferroptosis in MM.
In conclusion, Yan et al have provided a foundation for developing combination therapies for MM. The simultaneous targeting of STK17B and ferroptosis pathways represents an appealing strategy for MM treatment. Inhibition of STK17B could potentially lower the activation threshold for T-cell–mediated antitumor immunity, whereas ferroptosis inducers directly eliminate MM cells that resist conventional apoptosis, which would leverage both intrinsic (direct killing of tumor cells) and extrinsic (immune-mediated) antitumor mechanisms. However, it is unknown whether the STK17B inhibitor acts as a double whammy to also regulate antitumor immunity. Might the iron status of patients with MM influence their responsiveness to STK17B-targeted therapies? Could the dynamic evolution of MM clones during disease progression and treatment pressure alter STK17B expression? Answering these questions will benefit the integration of STK17B-ferroptosis targeting with established MM therapies, including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and chimeric antigen receptor T cells.
Conflict-of-interest disclosure: The author declares no competing financial interests.
