Insights into recent findings and clinical application of YAP and TAZ in cancer

Nature reviews. Cancer, Год журнала: 2023, Номер 23(8), С. 512 - 525

Опубликована: Июнь 12, 2023

Язык: Английский

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Therapeutic targeting of TEAD transcription factors in cancer

Trends in Biochemical Sciences, Год журнала: 2023, Номер 48(5), С. 450 - 462

Опубликована: Янв. 26, 2023

Язык: Английский

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Vascular smooth muscle cells in intimal hyperplasia, an update

Frontiers in Physiology, Год журнала: 2023, Номер 13

Опубликована: Янв. 4, 2023

Arterial occlusive disease is the leading cause of death in Western countries. Core contemporary therapies for this include angioplasties, stents, endarterectomies and bypass surgery. However, these treatments suffer from high failure rates due to re-occlusive vascular wall adaptations restenosis. Restenosis following surgery largely intimal hyperplasia. Intimal hyperplasia develops response vessel injury, inflammation, smooth muscle cells dedifferentiation, migration, proliferation secretion extra-cellular matrix into vessel’s innermost layer or intima. In review, we describe current state knowledge on origin mechanisms underlying dysregulated hyperplasia, present new avenues research targeting VSMC phenotype proliferation.

Язык: Английский

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Direct and selective pharmacological disruption of the YAP–TEAD interface by IAG933 inhibits Hippo-dependent and RAS–MAPK-altered cancers

Nature Cancer, Год журнала: 2024, Номер 5(7), С. 1102 - 1120

Опубликована: Апрель 2, 2024

The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available pharmacologic agents bind into lipid pocket TEAD, targeting indirectly via allosteric changes. However, consequences a direct pharmacological disruption interface between and TEADs remain largely unexplored. Here, we present IAG933 its analogs as potent first-in-class selective disruptors with suitable properties to enter clinical trials. Pharmacologic abrogation all four TEAD paralogs resulted in eviction from chromatin reduced Hippo-mediated transcription induction cell death. In vivo, deep tumor regression was observed Hippo-driven mesothelioma xenografts at tolerated doses animal models well Hippo-altered cancer outside mesothelioma. Importantly this also extended larger indications, such lung, pancreatic colorectal cancer, combination RTK, KRAS-mutant MAPK inhibitors, leading more efficacious durable responses. Clinical evaluation is underway.

Язык: Английский

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Beyond controlling cell size: functional analyses of S6K in tumorigenesis

Cell Death and Disease, Год журнала: 2022, Номер 13(7)

Опубликована: Июль 25, 2022

Abstract As a substrate and major effector of the mammalian target rapamycin complex 1 (mTORC1), biological functions ribosomal protein S6 kinase (S6K) have been canonically assigned for cell size control by facilitating mRNA transcription, splicing, synthesis. However, accumulating evidence implies that diverse stimuli upstream regulators modulate S6K activity, leading to activation plethora downstream substrates distinct pathobiological functions. Beyond controlling size, simultaneously plays crucial roles in directing apoptosis, metabolism, feedback regulation its signals. Thus, we comprehensively summarize emerging regulators, substrates, mouse models, clinical relevance, candidate inhibitors shed light on as potential therapeutic cancers.

Язык: Английский

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Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK

Biophysical Reviews, Год журнала: 2023, Номер 15(2), С. 163 - 181

Опубликована: Апрель 1, 2023

Neurodevelopmental disorders (NDDs) and cancer share proteins, pathways, mutations. Their clinical symptoms are different. However, individuals with NDDs have higher probabilities of eventually developing cancer. Here, we review the literature ask how shared features can lead to different medical conditions why having an NDD first increase chances malignancy. To explore these vital questions, focus on dysregulated PI3K/mTOR, a major brain cell growth pathway in differentiation, MAPK, critical proliferation, hallmark Differentiation is governed by chromatin organization, making aberrant remodelers highly likely agents NDDs. Dysregulated organization accessibility influence lineage specific types at embryonic development stages. PAK1, pivotal roles cancer, also regulates MAPK. We review, clarify, connect pathways proliferation differentiation highlight PAK1 role MAPK regulation. Exactly activation controls development, remodeler components, e.g., BAF170 encoded

Язык: Английский

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On a sugar high: Role of O-GlcNAcylation in cancer

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(11), С. 105344 - 105344

Опубликована: Окт. 12, 2023

Recent advances in the understanding of molecular mechanisms underlying cancer progression have led to development novel therapeutic targeting strategies. Aberrant glycosylation patterns and their implication gained increasing attention as potential targets due critical role regulating tumor-specific pathways that contribute cell survival, proliferation, progression. A special type has been gaining momentum research is modification nuclear, cytoplasmic, mitochondrial proteins, termed O-GlcNAcylation. This protein catalyzed by an enzyme called O-GlcNAc transferase (OGT), which uses final product Hexosamine Biosynthetic Pathway (HBP) connect altered nutrient availability changes cellular signaling multiple aspects tumor Both its OGT are highly elevated fulfill crucial many hallmarks cancer. In this review, we present discuss latest findings elucidating involvement

Язык: Английский

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Targeting Hippo signaling in cancer: novel perspectives and therapeutic potential

MedComm, Год журнала: 2023, Номер 4(5)

Опубликована: Окт. 1, 2023

As highly conserved among diverse species, Hippo signaling pathway regulates various biological processes, including development, cell proliferation, stem function, tissue regeneration, homeostasis, and organ size. Studies in the last two decades have provided a good framework for how these fundamental functions of are tightly regulated by network with numerous intracellular extracellular factors. The pathway, when dysregulated, may lead to wide variety diseases, especially cancer. There is growing evidence demonstrating that dysregulated closely associated tumorigenesis, cancer invasion, migration, as well drug resistance. Therefore, considered an appealing therapeutic target treatment Promising novel agents targeting cancers recently emerged. These shown antitumor activity multiple models demonstrated potential treatment. However, detailed molecular basis signaling-driven tumor biology remains undefined. Our review summarizes current advances understanding mechanisms which drives tumorigenesis confers We also propose strategies future preclinical clinical development this pathway.

Язык: Английский

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Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Ноя. 13, 2023

Abstract Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and co-activators. Deregulation these regulatory molecules is associated with state transitions, which turn accountable for diverse maladies, including developmental disorders, metabolic most significantly, cancer. A decade back factors, key enablers disease development, were historically viewed as ‘undruggable’; however, intervening years, a wealth literature validated they can be targeted indirectly through transcriptional co-activators, their confederates various physiological molecular processes. These along have ability to initiate modulate genes necessary normal functions, whereby, deregulation such may foster tissue-specific phenotype. Hence, it essential analyze how co-activators specific multilateral processes coordination other factors. The proposed review attempts elaborate an in-depth account involvement regulation, context-specific contributions pathophysiological conditions. This also addresses issue has not been dealt comprehensive manner hopes direct attention towards future research will encompass patient-friendly therapeutic strategies, where drugs targeting enhanced benefits reduced side effects. Additional insights into currently available interventions constraints eventually reveal multitudes advanced targets aiming amelioration good patient prognosis.

Язык: Английский

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An update on the role of Hippo signaling pathway in ischemia-associated central nervous system diseases

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 162, С. 114619 - 114619

Опубликована: Март 31, 2023

The most frequent reason of morbidity and mortality in the world, cerebral ischemia sets off a chain molecular cellular pathologies that associated with some central nervous system (CNS) disorders mainly including ischemic stroke, Alzheimer's disease (AD), Parkinson's (PD), epilepsy other CNS diseases. In recent times, despite significant advancements treatment pathological processes underlying various neurological illnesses, effective therapeutic approaches are specifically targeted to minimizing damage such diseases remain absent. Hippo signaling pathway, characterized by enzyme linked reactions between MSTI/2, LAST1/2, YAP or TAZ proteins, controls cell division, survival, differentiation, as well being engaged variety biological activities, development transformation system. Recently, accumulating studies demonstrated pathway takes part AD, PD, etc., but not limited oxidative stress, inflammatory response, blood-brain barrier damage, mitochondrial disorders, neural cells death. Thus, it's crucial understand basis for determining potential new targets against ischemia-associated Here, we discuss latest advances deciphering highlight targeting treating

Язык: Английский

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