Targeting mutations in cancer

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(8)

Published: April 14, 2022

Targeted therapies have come to play an increasingly important role in cancer therapy over the past two decades. This success has been made possible large part by technological advances sequencing, which greatly advanced our understanding of mutational landscape human and genetic drivers present individual tumors. We are rapidly discovering a growing number mutations that occur targetable pathways, thus tumor testing become component choice appropriate therapies. dramatically transformed treatment outcomes disease prognosis some settings, whereas other oncologic contexts, targeted approaches yet demonstrate considerable clinical efficacy. In this Review, we summarize current knowledge range cancers, including hematologic malignancies solid tumors such as non-small cell lung breast cancer. outline seminal examples druggable targeting modalities address research challenges must be overcome maximize therapeutic benefit.

Language: Английский

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CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Jan. 11, 2021

Abstract Epigenetic alterations play an important role in tumor progression of diffuse large B-cell lymphoma (DLBCL). However, the biological relevance epigenetic gene mutations on microenvironment remains to be determined. The core set genes relating histone methylation ( KMT2D , KMT2C EZH2 ), acetylation CREBBP EP300 DNA TET2 and chromatin remodeling ARID1A ) were detected training cohort 316 patients by whole-genome/exome sequencing (WGS/WES) validation 303 with newly diagnosed DLBCL targeted sequencing. Their correlation peripheral blood immune cells clinical outcomes assessed. Underlying mechanisms investigated both vitro vivo. Among all 619 patients, somatic (19.5%) most frequently observed, followed (8.7%), (8.4%), (8.2%), (7.8%), (6.8%), (2.9%). them, / significantly associated decreased absolute lymphocyte-to-monocyte ratios, as well inferior progression-free overall survival. In B-lymphoma cells, mutation or knockdown inhibited H3K27 acetylation, downregulated FBXW7 expression, activated NOTCH pathway, downstream CCL2/CSF1 resulting tumor-associated macrophage polarization M2 phenotype cell proliferation. murine models, xenografted tumors bearing presented lower higher recruitment, more rapid growth than those wild-type control via FBXW7-NOTCH-CCL2/CSF1 axis. Our work thus contributed understanding aberrant regulation alternative mechanism DLBCL.

Language: Английский

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Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends

Journal of Biomedical Science, Journal Year: 2021, Volume and Issue: 28(1)

Published: April 11, 2021

Abstract Epigenetic drug discovery field has evidenced significant advancement in the recent times. A plethora of small molecule inhibitors have progressed to clinical stage investigations and are being explored exhaustively ascertain conclusive benefits diverse malignancies. Literature precedents indicates that substantial amount efforts were directed towards use epigenetic tools monotherapy as well combination regimens at level, however, preclinical/preliminary explorations inclined identification prudent approaches can leverage anticancer potential single agents only. This review article presents an update FDA approved drugs along with undergoing different cancer types. detailed discussion pragmatic strategies expected steer progress therapy through implementation emerging such PROTACS CRISPR/Cas9 logical ways for scaffold fabrication selectively approach enzyme isoforms pursuit garnering amplified antitumor effects been covered. In addition, compilation also rational construction multi-targeting assemblages employing previously identified pharmacophores alternatives therapy.

Language: Английский

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The Role of EREG/EGFR Pathway in Tumor Progression

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(23), P. 12828 - 12828

Published: Nov. 27, 2021

Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal (CRC). Epiregulin (EREG) is one EGFR low expressed in most normal tissues. Elevated EREG cancers mainly activates signaling pathways promotes progression. Notably, a higher expression level CRC with wild-type Kirsten rat sarcoma (KRAS) related better efficacy therapeutic treatment. By contrast, resistance anti-EGFR therapy was driven expression, aberrant genetic mutation signal pathway alterations. Additionally, overexpression non-small cell (NSCLC) anticipated be target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that derived from macrophages NSCLC EGFR-TKI The emerging events EREG-mediated promotion signals are generated autocrine paracrine loops arise epithelial cells, fibroblasts, microenvironment (TME). TME crucial element development types drug resistance. regulation EREG/EGFR depends on distinct oncogenic driver mutations contexts allows specific pharmacological targeting alone or combinational treatment tailored therapy. Novel strategies EREG/EGFR, tumor-associated macrophages, alternative oncoproteins under undergoing clinical trials. In this review, we summarize outcomes interaction ligand TME. may potential combined other targets combat cancers.

Language: Английский

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Epigenetics of glioblastoma multiforme: From molecular mechanisms to therapeutic approaches

Seminars in Cancer Biology, Journal Year: 2020, Volume and Issue: 83, P. 100 - 120

Published: Dec. 25, 2020

Language: Английский

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Benzimidazole and its derivatives as cancer therapeutics: The potential role from traditional to precision medicine

Acta Pharmaceutica Sinica B, Journal Year: 2022, Volume and Issue: 13(2), P. 478 - 497

Published: Sept. 21, 2022

Cancer is the second leading cause of mortality globally which remains a continuing threat to human health today. Drug insensitivity and resistance are critical hurdles in cancer treatment; therefore, development new entities targeting malignant cells considered high priority. Targeted therapy cornerstone precision medicine. The synthesis benzimidazole has garnered attention medicinal chemists biologists due its remarkable pharmacological properties. Benzimidazole heterocyclic pharmacophore, an essential scaffold drug pharmaceutical development. Multiple studies have demonstrated bioactivities derivatives as potential anticancer therapeutics, either through specific molecules or non-gene-specific strategies. This review provides update on mechanism actions various structure‒activity relationship from conventional healthcare bench clinics.

Language: Английский

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Anticancer Activity of Natural and Synthetic Chalcones

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(21), P. 11306 - 11306

Published: Oct. 20, 2021

Cancer is a condition caused by many mechanisms (genetic, immune, oxidation, and inflammatory). Anticancer therapy aims to destroy or stop the growth of cancer cells. Resistance treatment theleading cause inefficiency current standard therapies. Targeted therapies are most effective due low number side effects resistance. Among small molecule natural compounds, flavonoids particular interest for theidentification new anticancer agents. Chalcones precursors all have biological activities. The activity chalcones ability these compounds act on targets. Natural chalcones, such as licochalcones, xanthohumol (XN), panduretin (PA), loncocarpine, been extensively studied modulated. Modification basic structure in order obtain with superior cytotoxic properties has performed modulating aromatic residues, replacing residues heterocycles, obtaining hybrid molecules. A huge chalcone derivatives diaryl ether, sulfonamide, amine obtained, their presence being favorable activity. amino group aminochalconesis always antitumor This why molecules different nitrogen hetercycles obtained. From these, azoles (imidazole, oxazoles, tetrazoles, thiazoles, 1,2,3-triazoles, 1,2,4-triazoles) importance identification

Language: Английский

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Oxidative Stress: The Role of Antioxidant Phytochemicals in the Prevention and Treatment of Diseases

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3264 - 3264

Published: March 13, 2024

Oxidative stress, characterized by an imbalance favouring oxidants over antioxidants, is a key contributor to the development of various common diseases. Counteracting these considered effective strategy mitigate levels oxidative stress in organisms. Numerous studies have indicated inverse correlation between consumption vegetables and fruits risk chronic diseases, attributing health benefits presence antioxidant phytochemicals foods. Phytochemicals, present wide range foods medicinal plants, play pivotal role preventing treating diseases induced working as antioxidants. These compounds exhibit potent antioxidant, anti-inflammatory, anti-aging, anticancer, protective properties against cardiovascular diabetes mellitus, obesity, neurodegenerative conditions. This comprehensive review delves into significance averting managing elucidating sources invaluable elements. Additionally, it provides summary recent advancements understanding associated with phytochemicals.

Language: Английский

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Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Biology, Journal Year: 2021, Volume and Issue: 10(9), P. 854 - 854

Published: Aug. 31, 2021

5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and preferred first-line option metastatic cancer patients in combination with oxaliplatin FOLFOX, or irinotecan FOLFIRI regimens. Despite success to a certain extent, incidence of failure attributed resistance is still reported many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic acquired, primarily driven dysregulation various components distinct pathways. In recent years, it has been established that 5-FU akin multidrug alterations drug transport, evasion apoptosis, changes cell cycle DNA-damage repair machinery, regulation autophagy, epithelial-to-mesenchymal transition, stem involvement, microenvironment interactions, miRNA dysregulations, epigenetic alterations, well redox imbalances. Certain mechanisms are 5-FU-specific have also ascertained include upregulation thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, downregulation thymidine phosphorylase. Indeed, successful modulation these game plan numerous studies had employed small molecule inhibitors, plant-based molecules, non-coding RNA regulators effectively reverse cells. It hoped would provide fundamental knowledge further our understanding prior developing novel drugs near future synergistically work potentiate its antitumor effects improve patient’s overall survival.

Language: Английский

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GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy

Theranostics, Journal Year: 2021, Volume and Issue: 11(16), P. 7844 - 7868

Published: Jan. 1, 2021

Radiotherapy is one of the curative treatment options for localized prostate cancer (PCa).The potential radiotherapy mediated by irradiation-induced oxidative stress and DNA damage in tumor cells.However, PCa radiocurability can be impeded resistance mechanisms normal tissue toxicity.Metabolic reprogramming major hallmarks progression therapy resistance.Specific metabolic features might serve as therapeutic targets radiosensitization biomarkers Ivyspring International Publisheridentifying patients most likely to respond radiotherapy.The study aimed characterize a role glutaminase (GLS)-driven glutamine catabolism prognostic biomarker target radiosensitization.Methods: We analyzed primary cell cultures radioresistant (RR) derivatives conventional lines gene expression assays identify molecular traits associated with radiation resistance.Relative radiosensitivity were 2-D 3-D clonogenic analyses.Targeting (Gln) metabolism was achieved Gln starvation, knockdown, chemical inhibition.Activation response (DDR) autophagy assessed expression, western blotting, fluorescence microscopy.Reactive oxygen species (ROS) ratio reduced glutathione (GSH) oxidized (GSSG) luminescence probes, respectively.Cancer stem (CSC) properties investigated sphere-forming assay, CSC marker analysis, vivo limiting dilution assays.Single circulating cells (CTCs) isolated from blood array comparative genome hybridization.Expression levels GLS1 MYC tissues amino acid concentrations plasma correlated progression-free survival patients.Results: Here, we found that CSCs have high demand.GLS-driven serves not only energy production but also maintenance redox state.Consequently, depletion or inhibition critical regulators utilization, such GLS transcription factor results radiosensitization.On contrary, combination inhibitors irradiation does cause toxic effects on nonmalignant cells.Glutamine contributes through regulation alpha-ketoglutarate (α-KG)-dependent chromatin-modifying dioxygenase.The lack aldehyde dehydrogenase (ALDH) activity, decreases frequency populations reduces formation xenograft mouse models.Moreover, this shows activation ATG5-mediated strategy withstand radiation-mediated damage.In inhibition, blockade promising radiosensitization.High significantly correlate shorter prostate-specific antigen (PSA) doubling time.Furthermore, metabolism, MYC, decreased treated radiotherapy.Conclusions: Our findings demonstrate GLS-driven glutaminolysis radiosensitization.

Language: Английский

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