Oncotarget最新文献

Colorectal cancer remains the second leading cause of cancer-related deaths worldwide, highlighting the urgent need for more effective therapies and a deeper understanding of its molecular basis. Drug repurposing has gained traction as a viable strategy to target dysregulated oncogenic pathways. Statins, commonly prescribed for lowering cholesterol, have recently shown potential anti-cancer effects. In this study, we explore how statin treatment influences lipid metabolism, gene expression, and proteomic profiles in colorectal cancer models. Our findings provide direct evidence that statins selectively modulate key components of the Wnt/β-catenin signaling pathway, a major driver of adenoma formation, including members of the special AT-rich sequence-binding (SATB) protein family. We show that statin treatment downregulates SATB1, a known promoter of tumorigenesis in the context of Wnt activation, while simultaneously upregulating SATB2, which plays an opposing role. This reciprocal regulation shifts cellular phenotypes between epithelial and mesenchymal states in 3D spheroid models. Together, these results highlight the therapeutic potential of statins in colorectal cancer and support their consideration in drug repurposing approaches.

T_reg play a deleterious role in the tumor microenvironment by suppressing anti-tumor effector T cells. Deletion of T_reg can result in an enhanced anti-tumor response. It has been difficult to identify a cell surface antigen that is uniquely expressed on T_reg which can be targeted by a deleting mAb. We immunized mice with human T_reg cells which had been activated and expanded in vitro. One hybridoma (2B010) which recognized CD25 was identified. 2B010 demonstrated selective reactivity to T_reg cells that had been expanded in culture for 5 days, but displayed similar reactivity to a conventional anti-CD25 mAb on freshly expanded T_reg. 2B010 did not block the binding of IL-2 in the STAT5 phosphorylation assay and had no effect on the proliferation of T_conv or on T_reg suppressor function. It selectively reacted with T_reg activated in vivo during xeno-GVHD and produced a selective deletion of T_reg from mice undergoing xeno-GVHD. Administration of 2B010 to tumor bearing humanized mice resulted in a profound depletion of T_reg from the TME and activation of CD8⁺ T cells. No effect on tumor growth was observed. 2B010 represents a candidate for treatment of patients with cancer either alone or together with check point inhibitors.

Epidermal Growth Factor Receptor (EGFR) targeted therapies have yielded variable results in clinical trials for breast and head and neck cancers, despite EGFR overexpression in these malignancies. Primary resistance to these therapies is common, with secondary resistance often arising due to the overexpression of other receptor tyrosine kinases (RTKs) and increased downstream signaling from these RTKs. Additionally, non-RTK-driven mechanisms also contribute to anti-EGFR therapy resistance. This review highlights the role of AXL, MET, and RON families of RTKs in tumor progression and resistance to anti-EGFR therapies, focusing on breast and head and neck cancers. In breast cancer, the review discusses the intricate relationship between EGFR expression and therapeutic outcomes, emphasizing the challenges and potential strategies for enhancing EGFR-targeted treatments. It details how EGFR inhibition affects tumor progression and survival in head and neck cancer, noting that small molecule inhibitors and monoclonal antibodies, such as cetuximab, can lead to trans-activation of other RTKs. The review further explores non-RTK-driven resistance mechanisms in breast cancer, including EGFR activation through EGF-related ligands, nuclear localization of EGFR, and the overexpression of resistance-conferring proteins. In head and neck cancer, resistance is also mediated by TLR4-MyD88 signaling activation, loss of tumor suppressor genes like PTEN, activating mutations in PI3K, and involvement of STAT3. By synthesizing current insights on both RTK and non-RTK mediated resistance against anti-EGFR therapies, this review aims to guide future research and improve therapeutic strategies for these cancers.

Ferroptosis is a mode of cell death that relies on iron metabolism and lipid peroxidation. Preclinical and clinical studies indicate that ferroptosis suppresses tumor growth, and dysregulation of ferroptosis promotes treatment resistance in cancer. Hypoxia is a universal feature of solid tumors that is particularly relevant to prostate cancer (PCa), which arises in the hypoxic peripheral zone of the organ. Hypoxia has been implicated in resistance to ferroptosis and other forms of cell death, but how hypoxia impacts the sensitivity of PCa to ferroptosis inducing agents (FINs) has not been well studied. Here, we show that hypoxia dramatically reduces the sensitivity of PCa cell lines to mechanistically distinct FINs, Erastin (xCT inhibitor) and RLS3 (GPX4 inhibitor) by inducing lipid droplet (LD) accumulation. Transcriptomic analysis revealed that hypoxia significantly reduced the expression of genes related to incorporating polyunsaturated fatty acids into phospholipids (ACSL4, LPCAT3), and parallel lipidomic analysis demonstrated that hypoxia significantly decreased the levels of the ferroptosis-prone lipid class, phosphatidylethanolamine (PE) and increased production of neutral lipid species, cholesteryl ester (ChE (22:5)) and triglycerides (TG(48:1), TG:(50:4), and TG(58:4)). Targeting LD biogenesis and de novo lipogenesis did not alter sensitivity to RSL3 under hypoxia. These findings suggest that hypoxia promotes ferroptosis resistance in PCa by altering lipid metabolism at the transcriptional level, by producing lipids that are less susceptible to peroxidation, and at the cellular level, by increasing storage in LDs. Thus, manipulating LD dynamics represents a promising strategy to overcome hypoxia-induced resistance to ferroptosis and improve the success of PCa treatment.

Often associated with a poor prognosis, advanced urothelial carcinoma (aUC) has progressed to muscle-invasive or metastatic stages. Traditionally, chemotherapy has been the primary treatment for aUC, though its effectiveness in advanced stages remains limited. Recent developments have introduced promising therapies, notably the combination of enfortumab vedotin with pembrolizumab, which is now recommended as the first-line therapy following the EV-302 trial results. This combination has demonstrated significant improvements in survival rates. This review aims to explore the evolution of treatment strategies for aUC, emphasizing the shift towards immunotherapy and targeted therapies, and discusses the potential for optimized treatment algorithms to improve patient outcomes.

HER2 genomic alterations characterize a specific subset of NSCLC with potential therapeutic relevance. While most studies focus on populations from high-income countries, data from Latin America remains scarce. We retrospectively analyzed 13 HER2-mutated NSCLC cases from a single institution in Northeastern Brazil, integrating clinical, histopathological, immunohistochemical, and molecular findings. Predominant histological patterns included acinar and lepidic subtypes, with HER2 mutations primarily involving exon 20 insertions (A775_G776insYVMA) and frequent co-alterations in TP53, KRAS, and STK11. HER2 protein expression assessed by IHC showed low scores (0-2+) in most cases, while HER2 gene amplification was confirmed in one case by D-DISH and NGS. Tumor mutation burden was universally low. Treatment responses varied, with one patient receiving trastuzumab deruxtecan. Our findings highlight the molecular diversity and diagnostic challenges of HER2-mutated NSCLC in underrepresented populations, emphasizing the need for comprehensive molecular profiling and expanded access to targeted therapies.