Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(10), С. 5489 - 5489

Опубликована: Май 17, 2024

Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies peptides, along innovative approaches use of degraders protein interaction inhibitors, which recently demonstrated clinical progress potential in overcoming resistance. Nevertheless, kinase-targeted encounter significant hurdles, including drug resistance, greatly impacts benefits patients, well concerning toxicity when combined immunotherapy, restricts full utilization current treatment modalities. Despite these challenges, development remains highly promising. The extensively studied tyrosine family has 70% its stages development, while 30% inadequately explored. Computational technologies play a vital role accelerating novel repurposing existing drugs. Recent FDA-approved SMKIs underscore importance blood-brain barrier permeability long-term patient benefits. This review provides comprehensive summary recent based mechanisms action targets. We summarize latest developments new explore emerging inhibition from perspective. Lastly, we outline obstacles future prospects inhibition.

Язык: Английский

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Enhancing antitumor efficacy of CLDN18.2-directed antibody-drug conjugates through autophagy inhibition in gastric cancer

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Сен. 3, 2024

Abstract Claudin18.2 (CLDN18.2) is overexpressed in cancers of the digestive system, rendering it an ideal drug target for antibody-drug conjugates (ADCs). Despite many CLDN18.2-directed ADCs undergoing clinical trials, inconclusive underlying mechanisms pose a hurdle to extending utility these agents. In our study, αCLDN18.2-MMAE, ADC composed anti-CLDN18.2 monoclonal antibody and tubulin inhibitor MMAE, induced dose-dependent apoptosis via cleavage caspase-9/PARP proteins CLDN18.2-positive gastric cancer cells. It was worth noting that autophagy remarkably activated during αCLDN18.2-MMAE treatment, which characterized by accumulation autophagosomes, conversion marker LC3 from its form I II, complete autophagic flux. Inhibiting LY294002 enhanced αCLDN18.2-MMAE-induced cytotoxicity caspase-mediated apoptosis, indicating cytoprotective role ADC-treated Combination with significantly potentiated vivo antitumoral efficacy αCLDN18.2-MMAE. Besides, Akt/mTOR pathway inactivation demonstrated be implicated initiation αCLDN18.2-MMAE-treated conclusion, study highlighted groundbreaking investigation into mechanism ADC, focusing on crucial autophagy, providing novel insight treat combination inhibitor.

Язык: Английский

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Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets

Cancers, Год журнала: 2024, Номер 16(5), С. 901 - 901

Опубликована: Фев. 23, 2024

Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, genetic factors. No specific alterations are unequivocally linked to tumorigenesis. Current standard therapies surgical options, systemic chemotherapy, kinase inhibitors, like sorafenib regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint such as atezolizumab pembrolizumab, show efficacy, combination enhance clinical responses. Despite this, the treatment of (HCC) remains challenge, complex tumor ecosystem immunosuppressive microenvironment associated with it hamper efficacy available therapeutic approaches. This review explores current advanced approaches treat HCC, considering both known new potential targets, especially derived from proteomic analysis, which is today considered most approach. Exploring novel strategies, this discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), engineered antibodies. It then reports systematic analysis main ligand/receptor pairs molecular pathways reported be overexpressed cells, highlighting their limitations. Finally, TGFβ, one targets microenvironment.

Язык: Английский

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Hallmarks of cancer resistance

iScience, Год журнала: 2024, Номер 27(6), С. 109979 - 109979

Опубликована: Май 15, 2024

This review explores the hallmarks of cancer resistance, including drug efflux mediated by ATP-binding cassette (ABC) transporters, metabolic reprogramming characterized Warburg effect, and dynamic interplay between cells mitochondria. The role stem (CSCs) in treatment resistance regulatory influence non-coding RNAs, such as long RNAs (lncRNAs), microRNAs (miRNAs), circular (circRNAs), are studied. chapter emphasizes future directions, encompassing advancements immunotherapy, strategies to counter adaptive integration artificial intelligence for predictive modeling, identification biomarkers personalized treatment. comprehensive exploration these provides a foundation innovative therapeutic approaches, aiming navigate complex landscape enhance patient outcomes.

Язык: Английский

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PIK3CA mutation as an acquired resistance driver to EGFR-TKIs in non-small cell lung cancer: Clinical challenges and opportunities

Pharmacological Research, Год журнала: 2024, Номер 202, С. 107123 - 107123

Опубликована: Март 2, 2024

Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have significantly enhanced the treatment outcomes in non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, occurrence of acquired resistance to EGFR-TKIs is an unavoidable outcome observed these patients. Disruption PI3K/AKT/mTOR signaling pathway can contribute emergence TKIs cancer. The PIK3CA mutations following with lead against EGFR-TKIs. This review provides overview current perspectives regarding involvement development Furthermore, we outline state-of-the-art therapeutic strategies targeting We highlight role mutation as mechanism EGFR-mutant NSCLC. Crucially, explore PIK3CA-mediated cancer, aiming optimize effectiveness treatment.

Язык: Английский

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Multiple myeloma: signaling pathways and targeted therapy

Molecular Biomedicine, Год журнала: 2024, Номер 5(1)

Опубликована: Июль 4, 2024

Abstract Multiple myeloma (MM) is the second most common hematological malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, renal failure, and accumulation malignant cells. The pathogenesis MM involves interaction between cells marrow microenvironment through soluble cytokines cell adhesion molecules, which activate various signaling pathways such as PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, NF-κB pathways. Aberrant activation these contributes to proliferation, survival, migration, drug resistance making them attractive targets for therapeutic intervention. Currently, approved drugs targeting in are limited, with many inhibitors inducers still preclinical or clinical research stages. Therapeutic options include non-targeted like alkylating agents, corticosteroids, immunomodulatory drugs, proteasome inhibitors, histone deacetylase inhibitors. Additionally, targeted monoclonal antibodies, chimeric antigen receptor T bispecific T-cell engagers, antibodies being used treatment. Despite significant advancements treatment, disease remains incurable, emphasizing need development novel combined therapies based on emerging theoretical knowledge, technologies, platforms. In this review, we highlight key role progression treatment MM, exploring advances therapy potential treatments offer further insights improving management outcomes.

Язык: Английский

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Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11

Journal of Experimental & Clinical Cancer Research, Год журнала: 2024, Номер 43(1)

Опубликована: Апрель 13, 2024

The dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling plays a critical role in ferroptosis resistance and tumorigenesis. However, the precise underlying mechanisms still need to be fully understood. Endoplasmic reticulum oxidoreductase alpha (ERO1α) expression mTORC1-activated mouse embryonic fibroblasts, cancer cells, laryngeal squamous cell carcinoma (LSCC) clinical samples was examined by quantitative real-time PCR (qRT-PCR), western blotting, immunofluorescence (IF), immunohistochemistry. Extensive vitro vivo experiments were carried out determine ERO1α its downstream target, member 11 solute carrier family 7 (SLC7A11), mTORC1-mediated proliferation, angiogenesis, resistance, tumor growth. regulatory mechanism on SLC7A11 investigated via RNA-sequencing, cytokine array, an enzyme-linked immunosorbent assay, qRT-PCR, IF, luciferase reporter chromatin immunoprecipitation assay. combined therapeutic effect inhibition inducer imidazole ketone erastin (IKE) cells evaluated using line-derived xenografts, LSCC organoids, patient-derived xenograft models. is functional mTORC1. Elevated induced exerted pro-oncogenic roles upregulation SLC7A11. Mechanically, stimulated transcription activating interleukin-6 (IL-6)/signal transducer activator 3 (STAT3) pathway. Moreover, with treatment IKE exhibited synergistic antitumor effects tumors. ERO1α/IL-6/STAT3/SLC7A11 pathway crucial for growth, combining inducers novel effective mTORC1-related

Язык: Английский

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mTOR: Its Critical Role in Metabolic Diseases, Cancer, and the Aging Process

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(11), С. 6141 - 6141

Опубликована: Июнь 2, 2024

The mammalian target of rapamycin (mTOR) is a pivotal regulator, integrating diverse environmental signals to control fundamental cellular functions, such as protein synthesis, cell growth, survival, and apoptosis. Embedded in complex network signaling pathways, mTOR dysregulation implicated the onset progression range human diseases, including metabolic disorders diabetes cardiovascular well various cancers. also has notable role aging. Given its extensive biological impact, prime therapeutic for addressing these conditions. development inhibitors proven advantageous numerous research domains. This review delves into significance signaling, highlighting critical components this intricate that contribute disease. Additionally, it addresses latest findings on their clinical implications. emphasizes importance developing more effective next-generation with dual functions efficiently pathways. A comprehensive understanding will enable strategies managing diseases associated dysregulation.

Язык: Английский

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Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition

Journal of Hematology & Oncology, Год журнала: 2025, Номер 18(1)

Опубликована: Янв. 13, 2025

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, signaling molecules that interact promote growth therapeutic resistance. Elucidating the intricate interactions between cells TME crucial in understanding progression challenges. A critical process induced by epithelial-mesenchymal transition (EMT), wherein epithelial acquire mesenchymal traits, which enhance their motility invasiveness progression. By targeting various components TME, novel investigational strategies aim disrupt TME's contribution EMT, thereby improving efficacy, addressing resistance, offering a nuanced approach therapy. This review scrutinizes key players emphasizing avenues therapeutically components. Moreover, article discusses implications for resistance mechanisms highlights current toward modulation along with potential caveats.

Язык: Английский

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STIMULI-RESPONSIVE SUPRAMOLECULAR HYDROGELS FOR PACLITAXEL DELIVERY: PROGRESS AND PROSPECTS

Aspects of Molecular Medicine, Год журнала: 2025, Номер 5, С. 100062 - 100062

Опубликована: Янв. 5, 2025

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