PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: March 24, 2022

Cancer is a severe public health issue that leading cause of mortality globally. It also an impediment to improving life expectancy worldwide. Furthermore, the global burden cancer incidence and death continuously growing. Current therapeutic options are insufficient for patients, tumor complexity heterogeneity necessitate customized medicine or targeted therapy. critical identify potential targets. Aberrant activation PI3K/AKT/mTOR pathway has significant role in carcinogenesis. This review summarized oncogenic PI3K/Akt/mTOR alterations various hallmarks associated with pathway, such as cell proliferation, autophagy, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT), chemoresistance. Importantly, this provided recent advances inhibitor research. Overall, in-depth understanding association between tumorigenesis development therapies targeting will help make clinical decisions.

Language: Английский

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ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group

Annals of Oncology, Journal Year: 2022, Volume and Issue: 33(8), P. 750 - 768

Published: July 6, 2022

•Validated and sensitive ctDNA assays can be used to genotype advanced cancers select patients for targeted therapies.•Initial genotyping with should considered when rapid results are needed, tissue is unavailable.•ctDNA assay limited by false-negative results, lower sensitivity fusion events copy number changes.•Use of detect molecular residual disease not recommended, due lack evidence its clinical utility. Circulating tumour DNA (ctDNA) conducted on plasma rapidly developing a strong base use in cancer. The European Society Medical Oncology convened an expert working group review the analytical validity utility assays. For cancer, validated adequately have identifying actionable mutations direct therapy, may routine practice, provided limitations taken into account. Tissue-based testing remains preferred test many cancer patients, detecting changes, although routinely faster will clinically important, or biopsies possible inappropriate. Reflex following non-informative result, testing. In treated early-stage cancers, detection relapse, has high anticipating future relapse cancers. Molecular disease/molecular cannot recommended as currently there no directing treatment. Additional potential applications assays, under research development include responding therapy early dynamic changes levels, monitoring resistance before progression, screening asymptomatic people Recommendations reporting made.

Language: Английский

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Clonal dynamics of haematopoiesis across the human lifespan

Nature, Journal Year: 2022, Volume and Issue: 606(7913), P. 343 - 350

Published: June 1, 2022

Abstract Age-related change in human haematopoiesis causes reduced regenerative capacity 1 , cytopenias 2 immune dysfunction 3 and increased risk of blood cancer 4–6 but the reason for such abrupt functional decline after 70 years age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies haematopoietic cells across 10 subjects 0 to 81 age. Haematopoietic stem or multipotent progenitors (HSC/MPPs) accumulated a mean 17 mutations per year birth lost 30 base pairs telomere length. Haematopoiesis adults less than 65 was massively polyclonal, with high clonal diversity stable population 20,000–200,000 HSC/MPPs contributing evenly production. By contrast, individuals aged over 75 showed profoundly decreased diversity. In each older subjects, 30–60% accounted by 12–18 independent clones, 1–34% Most clones had begun their expansion before subject 40 old, only 22% known driver mutations. Genome-wide selection analysis estimated that between 34 12 non-synonymous were drivers, accruing at constant rates throughout life, affecting more genes identified cancers. Loss Y chromosome conferred selective benefits males. Simulations haematopoiesis, cell size acquisition conferring moderate fitness benefits, entirely explained structure elderly. Rapidly decreasing is universal feature humans, underpinned pervasive positive acting on many currently identified.

Language: Английский

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Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling

Cell stem cell, Journal Year: 2021, Volume and Issue: 28(8), P. 1428 - 1442.e6

Published: March 20, 2021

Language: Английский

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Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(8), P. 1155 - 1166

Published: July 14, 2022

Abstract Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over third people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map landscape inherited predisposition CH, increasing number germline associations with CH in European-ancestry populations 4 14. Genes at new loci implicate DNA damage repair ( PARP1 , ATM CHEK2 ), hematopoietic migration/homing CD164 ) myeloid oncogenesis SETBP1 ). Several were CH-subtype-specific including variants TCL1A that had opposite DNMT3A - versus TET2 -mutant two most common subtypes, proposing key roles for these development. Mendelian randomization analyses showed smoking longer leukocyte telomere length are causal risk factors increases risks myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation epigenetic ageing.

Language: Английский

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Acute myeloid leukaemia

The Lancet, Journal Year: 2023, Volume and Issue: 401(10393), P. 2073 - 2086

Published: April 15, 2023

Language: Английский

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Embracing cancer complexity: Hallmarks of systemic disease

Cell, Journal Year: 2024, Volume and Issue: 187(7), P. 1589 - 1616

Published: March 1, 2024

Language: Английский

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Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease

Journal of Molecular and Cellular Cardiology, Journal Year: 2021, Volume and Issue: 161, P. 98 - 105

Published: July 21, 2021

Language: Английский

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Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis

NEJM Evidence, Journal Year: 2023, Volume and Issue: 2(5)

Published: April 25, 2023

Clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia undetermined significance (CCUS) are defined by somatic mutations in genes associated with myeloid neoplasms (MN) at a variant allele fraction (VAF) ≥ 0.02, the absence presence cytopenia, respectively. CHIP/CCUS is highly prevalent adults defining predictors MN risk would aid clinical management research.

Language: Английский

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CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

Cells, Journal Year: 2020, Volume and Issue: 9(12), P. 2675 - 2675

Published: Dec. 12, 2020

Germline alterations in many genes coding for proteins regulating DNA repair and damage response (DDR) to double-strand breaks (DDSB) have been recognized as pathogenic factors hereditary cancer predisposition. The ATM-CHEK2-p53 axis has documented a backbone DDR hypothesized barrier against initiation. However, although CHK2 kinase coded by the CHEK2 gene expedites signal, its function activation of p53-dependent cell cycle arrest is dispensable. mutations rank among most frequent germline revealed genetic testing various predispositions, but their interpretation not trivial. From perspective variants, we review current knowledge related structure gene, kinase, clinical significance patients with breast, prostate, kidney, thyroid, colon cancers.

Language: Английский

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