Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects at least 10 million people worldwide and is associated with the development of T-cell lymphoma (TCL). The treatment of TCL remains challenging and new treatment options are urgently needed. With the goal of developing a novel therapeutic approach for TCL, we investigated the activity of the clinical formulation of oncolytic reovirus (Reolysin, Pelareorep) in TCL models. Our studies revealed that HTLV-1-negative TCL cells were highly sensitive to Reolysin-induced cell death, but HTLV-1-positive TCL cells were resistant. Consistent with these data, reovirus displayed significant viral accumulation in HTLV-1-negative cells, but failed to efficiently replicate in HTLV-1-positive cells. Transcriptome analyses of HTLV-1-positive vs. negative cells revealed a significant increase in genes associated with retroviral infection including interleukin-13 and signal transducer and activator of transcription 5 (STAT5). To investigate the relationship between HTLV-1 status and sensitivity to Reolysin, we infected HTLV-1-negative cells with HTLV-1. The presence of HTLV-1 resulted in significantly decreased sensitivity to Reolysin. Treatment with the JAK inhibitor ruxolitinib suppressed STAT5 phosphorylation and expression of the key anti-viral response protein MX1 and enhanced the anti-TCL activity of Reolysin in both HTLV-1-positive and negative cells. Our data demonstrate that the inhibition of the JAK/STAT pathway can be used as a novel approach to antagonize the resistance of HTLV-1-positive cells to oncolytic virus therapy.

Increased basal protein synthesis activity is a hallmark feature that distinguishes many types of malignant cells from their normal counterparts. The survival and proliferation of cancer cells are tightly linked to functional unfolded protein response (UPR) and endoplasmic reticulum (ER)-associated degradation (ERAD) pathways due to their high rates of protein synthesis. The evolutionarily conserved AAA+ ATPase valosin-containing protein (VCP)/p97 facilitates the extraction of proteins from organelles, chromatin, and protein complexes to target them for ubiquitin–proteasome system (UPS)-mediated degradation. p97 plays a key role in protein quality control and in the maintenance of protein homeostasis through its regulation of ERAD. The disruption of p97 activity leads to an accumulation of undegraded proteins, triggers the UPR, and can culminate in proteotoxic cell death. Given this, p97 inhibition offers an opportunity to selectively kill cancer cells that exhibit high basal protein synthesis rates. This review explores p97’s molecular structure, diverse cellular roles, and clinical potential with a particular focus on CB-5083 and CB-5339, the only p97 inhibitors to date that have advanced into clinical trials. We discuss their mechanisms of action, clinical trial outcomes, and the transformative potential of rational combination strategies to maximize their therapeutic potential. By integrating foundational biological insights with translational perspectives, we highlight p97 as a precision target for cancer treatment.

The NADPH oxidase 2 (NOX2) complex is a critical regulator of immune homeostasis. It is utilized by phagocytic leukocytes including neutrophils, monocytes, and macrophages to generate reactive oxygen species (ROS) that drive microbe clearance and modulate inflammatory responses. Within NOX2, the essential scaffold protein p47phox plays a pivotal role in orchestrating enzyme activation and facilitating the assembly and membrane translocation of cytosolic components of the complex. Tight regulation of p47phox activity is crucial, and its disruption is linked to a number of pathological conditions. Conversely, its hyperactivity contributes to oxidative stress, tissue damage, the progression of cardiovascular diseases, neurodegenerative disorders, inflammatory conditions, metabolic syndromes, and cancer. In this review, we detail the structural and functional roles of p47phox, mechanisms of its regulation, and its multifaceted contributions to disease pathogenesis. We explore the latest advances in p47phox-targeted therapeutic strategies, discuss current challenges in the field, highlight p47phox’s potential as a transformative target in redox biology and propose future directions to unlock its clinical utility.

Although cisplatin remains a backbone of standard-of-care chemotherapy regimens for a variety of malignancies, its use is often associated with severe dose-limiting toxicities (DLT). Notably, 30%–40% of patients treated with cisplatin-based regimens are forced to discontinue treatment after experiencing nephrotoxicity as a DLT. New approaches that simultaneously prevent renal toxicity while improving therapeutic response have the potential to make a major clinical impact for patients with multiple forms of cancer. Here, we report that pevonedistat (MLN4924), a first-in-class NEDDylation inhibitor, alleviates nephrotoxicity and synergistically enhances the efficacy of cisplatin in head and neck squamous cell carcinoma (HNSCC) models. We demonstrate that pevonedistat protects normal kidney cells from injury while enhancing the anticancer activity of cisplatin through a thioredoxin-interacting protein (TXNIP)-mediated mechanism. Cotreatment with pevonedistat and cisplatin yielded dramatic HNSCC tumor regression and long-term animal survival in 100% of treated mice. Importantly, the combination decreased nephrotoxicity induced by cisplatin monotherapy as evidenced by the blockade of kidney injury molecule-1 (KIM-1) and TXNIP expression, a reduction in collapsed glomeruli and necrotic cast formation, and inhibition of cisplatin-mediated animal weight loss. Inhibition of NEDDylation represents a novel strategy to prevent cisplatin-induced nephrotoxicity while simultaneously enhancing its anticancer activity through a redox-mediated mechanism. Significance: Cisplatin therapy is associated with significant nephrotoxicity, which limits its clinical use. Here we demonstrate that NEDDylation inhibition with pevonedistat is a novel approach to selectively prevent cisplatin-induced oxidative damage to the kidneys while simultaneously enhancing its anticancer efficacy. Clinical evaluation of the combination of pevonedistat and cisplatin is warranted.

Acute myeloid leukemia (AML) remains defined by therapeutic resistance, adverse genetic heterogeneity, and poor long-term survival, underscoring the need for mechanistically informed regimens that exploit core stress-adaptation liabilities. Polo-like kinase 1 (PLK1) is a central regulator of replication recovery and mitotic progression, yet direct PLK1 inhibitors have been limited by tolerability and incomplete target suppression. Here, we define a clinically actionable strategy that functionally targets PLK1 by combining inhibition of the AAA+ ATPase p97/valosin-containing protein with the hypomethylating agent decitabine (DAC). Using AML cell lines, primary patient specimens, and an orthotopic in vivo model, we show that the clinically relevant p97 inhibitor CB-5339 induces proteotoxic and replication stress, activates the unfolded protein response, and triggers apoptosis. Formal synergy analyses demonstrate that CB-5339 and DAC cooperate across molecular subtypes, including FLT3-ITD+, KMT2A-rearranged, and TP53-mutant AML, to reduce cell viability at pharmacologically relevant concentrations. Transcriptomic, biochemical, and genetic studies identify synergistic suppression of PLK1 as a central consequence of combination treatment, converting stress-dependent PLK1 reliance into a therapeutic vulnerability. Consistent with this mechanism, PLK1 knockdown phenocopies the antileukemic effects of the combination and enhances sensitivity to both agents. In vivo, CB-5339/DAC is well tolerated, significantly prolongs survival, reduces leukemic burden, and suppresses PLK1 in bone marrow blasts. Together, these data establish p97 inhibition as a rational means to exploit replication and proteotoxic stress in AML and provide strong rationale for clinical evaluation of CB-5339 plus DAC in high-risk disease. Significance: This study defines a clinically actionable strategy to overcome therapeutic resistance in AML by functionally suppressing PLK1 through combined p97 inhibition and hypomethylating therapy. By exploiting convergent proteotoxic and replication stress, the regimen produces robust, well-tolerated antileukemic activity across high-risk genetic subtypes, supporting near-term clinical evaluation.

Figure S5. Time course cell viability analysis following treatment with CB-5339, DAC, and the combination.