PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Aug. 18, 2023

Abstract The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, growth, and cycle progression. Growth factor signalling to transcription factors the PAM axis regulated by multiple cross-interactions with several other pathways, dysregulation of can predispose cancer development. most frequently activated human often implicated resistance anticancer therapies. Dysfunction components this such as hyperactivity PI3K, loss function PTEN, gain-of-function AKT, are notorious drivers treatment disease progression cancer. In review we highlight major dysregulations cancer, discuss results AKT mTOR inhibitors monotherapy co-administation antineoplastic agents clinical trials strategy for overcoming resistance. Finally, mechanisms targeted therapies, including immunology immunotherapies also discussed.

Language: Английский

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NF-κB in biology and targeted therapy: new insights and translational implications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 4, 2024

Abstract NF-κB signaling has been discovered for nearly 40 years. Initially, was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have that its role can be expanded to variety of mechanisms, biological processes, human diseases, treatment options. In this review, we first scrutinize the research process signaling, summarize composition, activation, regulatory mechanism signaling. We investigate interaction other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, TLR The physiological pathological states well intricate involvement inflammation, immune regulation, tumor microenvironment, are also explicated. Additionally, illustrate how is involved cancers, autoimmune cardiovascular metabolic neurological COVID-19. Further, discuss therapeutic approaches targeting IKK inhibitors, monoclonal antibodies, proteasome nuclear translocation DNA binding TKIs, non-coding RNAs, immunotherapy, CAR-T. Finally, provide an outlook field hope present stereoscopic, comprehensive will inform future clinical practice.

Language: Английский

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Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 388(22), P. 2058 - 2070

Published: May 31, 2023

AKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of inhibitor capivasertib, as an addition to fulvestrant therapy, patients with hormone receptor-positive advanced breast cancer are limited.

Language: Английский

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Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Oct. 2, 2023

The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, to maintain homeostasis. mTOR signaling cascade consists two distinct multi-subunit complexes named complex 1/2 (mTORC1/2). catalyzes the phosphorylation several critical proteins like AKT, C, insulin growth factor receptor (IGF-1R), 4E binding 1 (4E-BP1), ribosomal S6 (S6K), transcription EB (TFEB), sterol-responsive element-binding (SREBPs), Lipin-1, Unc-51-like autophagy-activating kinases. plays central role in regulating translation, lipid synthesis, nucleotide biogenesis lysosomes, nutrient sensing, signaling. emerging pieces evidence have revealed constitutive activation pathway due mutations/amplification/deletion either its (mTORC1 mTORC2) or upstream targets responsible for aging, neurological diseases, human malignancies. Here, we provide detailed structure mTOR, complexes, comprehensive regulators, as well downstream effectors cascades biomolecules, autophagy. Additionally, summarize potential long noncoding RNAs (lncRNAs) an important modulator Importantly, highlighted disorders, cancers, cancer stem cells, drug resistance. discuss developments therapeutic targeting with improved anticancer efficacy benefit patients clinics.

Language: Английский

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Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: July 6, 2023

Abstract Breast cancer is the second leading cause of death for women worldwide. The heterogeneity this disease presents a big challenge in its therapeutic management. However, recent advances molecular biology and immunology enable to develop highly targeted therapies many forms breast cancer. primary objective therapy inhibit specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, different growth factors have emerged as potential targets subtypes. Many drugs are currently undergoing clinical trials, some already received FDA approval monotherapy or combination with other treatment yet achieve promise against triple-negative (TNBC). In aspect, immune has come up promising approach specifically TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, adoptive cell transfer been extensively studied setting cancer, especially approved blockers chemotherapeutic treat several trials ongoing. This review provides an overview developments advancements immunotherapies treatment. successes, challenges, prospects were critically discussed portray their profound prospects.

Language: Английский

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Harnessing the potential of hydrogels for advanced therapeutic applications: current achievements and future directions

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: July 1, 2024

The applications of hydrogels have expanded significantly due to their versatile, highly tunable properties and breakthroughs in biomaterial technologies. In this review, we cover the major achievements potential therapeutic applications, focusing primarily on two areas: emerging cell-based therapies promising non-cell modalities. Within context cell therapy, discuss capacity overcome existing translational challenges faced by mainstream therapy paradigms, provide a detailed discussion advantages principal design considerations for boosting efficacy as well list specific examples different disease scenarios. We then explore drug delivery, physical intervention therapies, other areas (e.g., bioadhesives, artificial tissues, biosensors), emphasizing utility beyond mere delivery vehicles. Additionally, complement our latest progress clinical application outline future research directions, particularly terms integration with advanced biomanufacturing This review aims present comprehensive view critical insights into selection both tailored meet requirements diverse diseases situations.

Language: Английский

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Molecular biology of the cell

Journal of Education Health and Sport, Journal Year: 2022, Volume and Issue: 12(8), P. 730 - 926

Published: Aug. 23, 2022

The book is intended for students studying medical and biological specialties. CHAPTER I. EPIGENETICS INTRODUCTION science of epigenetics looks at the mechanisms molecular modifications histones DNA that can regulate gene activity without affecting nucleotide sequences in molecule. Recognized epigenetic regulators are methylation, post-translational histones, non-coding RNAs (nkRNAs). One most important differences between eukaryotic cells prokaryotes presence a complex nucleo-protein chromatin eukaryotes. It this form molecule stored our cells. On one hand, structural organization provides compact arrangement cell nucleus. other directly involved process regulating expression. At same time, nucleosome depicted Fig. 1 (a functional unit chromatin) considered as key component processes nucleus 8 histone proteins (octamers). consists two copies each H2A, H2B, H3 H4. chain, which includes 147 nucleotides, folds 1.65 times around octamer histones. nucleosomes arranged linear array along "beads on string". linker section connecting adjacent (transcriptionally inactive) sealed with H1-histone protein. length 30 nm. Moreover, site beginning transcription usually located inside nucleosome. Consequently, serves repressor, preventing initiation transcription. That is, total repression genes. In contrast, becomes possible result remodeling factors enable "dismantling" or otherwise alter their structure organization. Thus, (inactivation) genes begins wrapping nucleosome, liberation from (activation) involves freeing binding to unfolding by (Lorch Y., Kornberg R. D., 2017). Thanks mechanism, selective expression only those needed given time tissue possible. should be emphasized extends not transcription, but also associated molecule, such replication, mitotic division, repair double-strand breaks, maintenance telomeres. control various physiological pathological corresponding changing availability systems chromatin. scope application research methods rapidly expanding. Currently, we witnessing active introduction approaches field practical medicine aimed diagnosing treating dangerous human diseases. II. TRANSCRIPTION FACTORS For first existence was revealed basis discovery made it establish vitro purified RNA polymerase-II initiate template extract (Weil P. A. et al., 1979). Further fractionation identification general (GTF) required has identified similar rats, Drosophila, yeast substantiated assumption GTFs indeed "common" necessary transcribed polymerase highly conserved number organisms (Matsui T. 1980). We mention II because type enzyme ability synthesize mRNA. Whereas I responsible synthesis pro-rRNA, III tRNA RNAs. Meanwhile, regulation eukaryotes quite complex, since depends complexes (Burns L. G., Peterson C. L., 1997) covalent modification (Natsume-Kitatani Mamitsuka H., 2016). initiation, immediate target GTF well-defined promo zone gene. promotra eukaryotes, main elements regulatory distinguished. (bark promoter, see 2.1) attributed assembling (PIC), including TATA sequence above start (TSS ), an initiating (Inr) covering site. Promoters may include unit, initiator (Inr), both (Hampsey M., 1998). A third major element, downstream promoter element (DPE), originally described Drosophila about p.p. below TSS. DPE appears function conjunction Inr factor TFIID non-TATA promoters. According current research, cellular (main) promoters multicellular contain short nucleotides called cow (motifs) (e.g., block, lower (DPE)) recruit through common mechanism (Dreos 2021). authors report classes Inr+DPE present genome humans structurally other, different species organisms. studied box, box found 10-20% cortical Therefore, sequence, name known elements, include: BRE, MTE, TST sequences. BRE (TFIIB recognition element) motifs either (BREu) (BREd) box. TBP, demonstrate high levels conservatism range archaebacteria (Kadonaga J. T., 2012). doing so, BREu well BREd have positive negative effects activity. core (DPE) detected analysis Drosophila. MTE (motif ten element), front DPE, overrepresented "motif 10" then discovered, promoter. exhibit humans, appear recognized subunits TFIID, TAF resemble structure. turn, TCT regulates ribosomal protein humans. Although there no universal all promoters, concept nuclear defined minimum stretch sufficient accurately 2012; Haberle V., Stark A., 2018). noted results modern will constantly supplement list new components example, DNA-replicatedrelated (DRE), Ohler 1,6 7 (Danino Y. M. 2015; authors, bark transformed course evolution. Due this, modulated composition elements. Such modulation achieved emergence combinations additional level realized. To summarize facts, initiated specific position, Transcription Initiation Site (TSS), 5' end TSS embedded spanning 50 base pairs platform related (GTFs). Regulatory low basal activity, further activated, generally more distally enhancers (discussed below). Enhancers bind factors, cofactors, enhance III. CELL SIGNALING PATHWAYS organism, work regulated large signals. These signals formed organism itself, reflecting needs living (metabolic state, stages development, differentiation, reproduction), reaction external environment. implementation these encompasses biochemical lead cell's perception signal response. something receptor, turn response signal. receptor recognizes signal, interprets specificity translates into intracellular signaling molecules, cascade phosphorylation, pathways. soon (ligand) binds its – complementary transmembrane cell. Growth hormones, cytokines, neurotransmitters, extracellular matrix, etc. chemical nature ligands diverse, small molecules lipids (prostaglandins, steroid hormones), (for peptide cytokines chemokines, growth factors)., polymers sugars β-glucan zymosan) proteoglycans), nucleic acids, Binding ligand induces conformational changes translated activating cascades secondary messengers (kinases, phosphatases, GTPases, ions cAMP, cGMP, diacylglycerol, etc.). message transmitted membrane nucleus, where expression, subsequent translation targeting organelles triggered. There types receptors (transmembrane) receptors. Membrane plasma separate domain ligand, hydrophobic nature, cytoplasmic domain. Cell surface divided G-protein-bound receptors, tyrosine kinase-bound ionotropic When binds, undergo activate enzymatic domain, kinases, phosphatases adapter proteins. covalently bound capable producing transmission. Intracellular (estrogen glucocorticoid progesterone retinoic acid thyroid hormone etc.), membranes (mitochondria, endoplasmic reticulum Golgi apparatus). information received receptor) targets. All path transmission However, certain set effector proteins, enzymes substrates implement pathway (signaling cascade). Recently, however, been growing evidence themselves play extremely role signaling, theso-called scaffold ("platform proteins", adaptor proteins), coordinate assembly multicomponent complexes. Scaffold several single thereby modulating efficiency bringing closer together, direct flow cell, activating, coordinating events networks (Skovorodnikova P.A. literature, described, cover wide functions. This group three categories (Fig. 1): simple functionally dependent (adaptors), larger multi-domain designed (scaffold⁄anchoring proteins) specialized localizing proteins-components pathways (docking ( Buday Tompa P, 2010) platforms increases selectivity pathway, allows formation feedback. e ultimate ultimately allow resulting converted change (Brivanlou Darnell E., 2002). Most eventually activation repressors sequence. Eukaryotic like takes place cytoplasm. Signal multifactorial system, based nodular special cascades. none isolation. interaction inevitable complexes, when system perceives combination stimuli (hormones, pathogenic ligands), preserves accuracy (Saini N., Sarin relatively development mammals Combinations action determine decisions fate differentiation ontogenesis (Li R., Elowitz M.V., 2019; de Roo Staal F. 2020) malignancy (Dreesen O., Brivanlou A.N., 2007; Skovorodnikova Consider some medically important. IV. MOLECULAR BIOLOGY OF THE TUMOR: MECHANISMS INITIATION, PROMOTION AND PROGRESSION Tumor diseases occupy leading place, terms morbidity mortality. despite advances study genetic patterns, many unresolved questions remain. spectrum markers makes diagnose, predict course, degree malignancy, rate tumor progression therapy. occur characterized stability, they dynamic profile - appearance clones properties. heterogeneity simultaneously complicates strategy managing patients, creating prerequisites characteristics

Language: Английский

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Molecular and functional imaging in cancer-targeted therapy: current applications and future directions

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Feb. 27, 2023

Targeted anticancer drugs block cancer cell growth by interfering with specific signaling pathways vital to carcinogenesis and tumor rather than harming all rapidly dividing cells as in cytotoxic chemotherapy. The Response Evaluation Criteria Solid Tumor (RECIST) system has been used assess response therapy via changes the size of target lesions measured calipers, conventional anatomically based imaging modalities such computed tomography (CT), magnetic resonance (MRI), other methods. However, RECIST is sometimes inaccurate assessing efficacy targeted because poor correlation between treatment-induced necrosis or shrinkage. This approach might also result delayed identification when does confer a reduction size. Innovative molecular techniques have gained importance dawning era they can visualize, characterize, quantify biological processes at cellular, subcellular, even level anatomical level. review summarizes different pathways, various techniques, developed probes. Moreover, application for evaluating treatment related clinical outcome systematically outlined. In future, more attention should be paid promoting translation sensitivity biocompatible particular, multimodal technologies incorporating advanced artificial intelligence comprehensively accurately cancer-targeted therapy, addition RECIST-based

Language: Английский

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A review of Glycogen Synthase Kinase-3 (GSK3) inhibitors for cancers therapies

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 253, P. 127375 - 127375

Published: Oct. 13, 2023

Language: Английский

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Aging, oxidative stress and degenerative diseases: mechanisms, complications and emerging therapeutic strategies

Biogerontology, Journal Year: 2023, Volume and Issue: 24(5), P. 609 - 662

Published: July 30, 2023

Language: Английский

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