Kinases Phosphatases, Volume 3, Issue 2 (June 2025) – 4 articles

Bruton’s tyrosine kinase (BTK) is a key signaling molecule involved in both hematological malignancies and solid tumors. In B-cell malignancies such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), BTK mediates B-cell receptor signaling, promoting tumor survival and proliferation, leading to the development of BTK inhibitors like ibrutinib that improve patient outcomes. In solid tumors, BTK isoforms, particularly p65BTK, contribute to tumor growth and therapy resistance, with inhibition showing promise in cancers like colorectal, ovarian, and non-small cell lung cancer. BTK also influences the tumor microenvironment by modulating immune cells such as myeloid-derived suppressor cells and tumor-associated macrophages, aiding immune evasion. BTK inhibition can enhance anti-tumor immunity and reduce inflammation-driven tumor progression. Additionally, BTK contributes to tumor angiogenesis, with inhibitors like ibrutinib showing anti-angiogenic effects. Beyond cancer, BTK is linked to aging, where its modulation may reduce senescent cell accumulation and preserve cognitive function. This review explores BTK’s dual role, focusing on its oncogenic effects and potential impact on aging processes. We also discuss the use of BTK inhibitors in cancer treatment and their potential to address age-related concerns, providing a deeper understanding of BTK as a therapeutic target and mediator in the complex relationship between cancer and aging. Full article

Kinase inhibitors are small molecules that block kinase activity and have significant applications in both therapy and diagnostics. Recent studies suggest that these inhibitors hold great potential as targets for treating a range of diseases, including autoimmune disorders, cardiovascular conditions, cancer, and inflammatory diseases like ulcerative colitis. Ongoing research focuses on developing effective carriers for tyrosine kinase inhibitors (TKIs) to enhance treatment outcomes while reducing side effects. The nano-scale drug carriers have demonstrated the ability to encapsulate a wide range of imaging and therapeutic agents, enhancing tumor diagnosis and treatment. Notably, the incorporation of drugs with poor pharmacokinetics into nanocarriers enhances their solubility and stability, offering a renewed opportunity to assess their full therapeutic potential. The entrapped agents can be released in a controlled manner to maintain a specific drug concentration within a treatment framework or triggered by specific stimuli such as time or pH to target particular tissues or cells. The multifunctionality of nanosystems offers a promising avenue for developing innovative tyrosine kinase inhibitor (TKI) delivery strategies that serve as alternative treatment options for cancer and other inflammatory diseases. This review aims to provide a comprehensive overview of innovative nano-scale delivery systems for TKIs, both as standalone treatments and in combination with other therapeutic agents or drug delivery approaches. We discuss their comparative advantages and limitations for future small-molecule TKIs research. Full article

Melanoma, known for its aggressive nature and propensity for developing drug resistance, remains a significant clinical challenge. The emergence of resistance to both targeted therapies (like BRAF/MEK inhibitors) and immunotherapies is a major obstacle to achieving durable responses and improving patient survival. HDACs, a class of epigenetic enzymes, modulate gene expression and chromatin structure by removing acetyl groups from histone and non-histone proteins. In melanoma, aberrant HDAC activity contributes to resistance through multiple mechanisms. HDACs influence key oncogenic signaling pathways frequently dysregulated in melanoma, such as the MAPK, PI3K/AKT, and WNT/β-catenin cascades. By altering the activity of these pathways, HDACs promote the survival and proliferation of melanoma cells even in the presence of therapy. Beyond their direct effects on tumor cells, HDACs also play a crucial role in shaping the tumor microenvironment. They can suppress anti-tumor immune responses by reducing immune cell infiltration, modulating cytokine production, and fostering an immunosuppressive milieu. This further contributes to resistance to immunotherapies. Given the central role of HDACs in these resistance mechanisms, HDAC inhibitors (HDACis) have emerged as potential therapeutic agents to restore drug sensitivity. HDACis can induce cell death, inhibit proliferation, and enhance immune responses in melanoma cells. Preclinical and clinical studies have explored the combination of HDACis with existing therapies to overcome resistance. While promising, the clinical application of HDACis is accompanied by challenges, including toxicity, the need for biomarkers to predict response, and the optimization of combination strategies. Ongoing research is dedicated to developing more selective and potent HDACis and to better understand how to effectively incorporate them into melanoma treatment regimens. This review provides a comprehensive overview of the multifaceted ways in which HDACs contribute to melanoma drug resistance and discusses the potential of HDAC-targeted therapies to improve patient outcomes. Full article

T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive neoplastic malignancy characterised by the accumulation of multiple oncogenic and epigenetic alterations in haematopoietic T-cell precursors leading to their uncontrolled proliferation and accumulation in the bone marrow. For many years it has been established that the occurrence of activating mutations, alterations in transcription factors expression, impairment in cell cycle regulators, and hyperactivation of NOTCH1 signalling play prominent roles in the pathogenesis of this disease. Recently, the introduction of high-resolution screening and next-generation sequencing platforms revealed that T-cell progenitors accumulate additional mutations, affecting protein kinase signalling, protein translation, and epigenetic control mechanisms, providing novel attractive targets for therapy. While the contributions of direct genomic events are well understood as causative agents of hyperactive kinase signalling pathways, the epigenetic rewiring of kinase signalling cascades via DNA methylation, histone post-translational modifications, and non-coding miRNAs remains less well explored. In this review, we provide novel perspectives on epigenetic regulatory aspects of kinase signalling heterogeneity in T-ALL pathogenesis and therapeutic outcomes. Full article