Unveiling the role of KRAS in tumor immune microenvironment

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 171, P. 116058 - 116058

Published: Jan. 2, 2024

Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as "undruggable". KRAS mutations frequently occur in multiple cancers including non-small cell lung cancer(NSCLC), colorectal cancer(CRC) and pancreatic ductal adenocarcinoma(PDAC), functioning a "molecule switch" determining activation of various oncogenic signaling pathways. Except for its intrinsic pro-tumorigenic role, alteration also exhibits an unique immune signature characterized by elevated PD-L1 level high tumor mutational burden(TMB). mutation shape suppressive microenvironment impeding effective T cells infiltration recruiting myeloid-derived suppressor cells(MDSCs), regulatory cells(Tregs), cancer associated fibroblasts(CAFs). In checkpoint inhibitor(ICI) era, NSCLC patients with mutated tend to be more responsive ICI than intact KRAS. The hallmark is existence kinds co-mutations. Different types co-alterations have distinct microenvironment(TME) signatures responses ICI. TP53 co-mutation possess "hot" TME achieve higher response immunotherapy while other loss function correlated "colder" poor outcome ICI-based therapy. groundbreaking discovery G12C inhibitors significantly improved outcomes this subtype even though efficacy was limited patients. restore TME, creating opportunity combinations However, inevitable challenge drug resistance. Promising combination strategies such SHP2 approach deserve further exploration because their modulatory effect.

Language: Английский

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Unveiling the potential effects of resveratrol in lung cancer treatment: Mechanisms and nanoparticle-based drug delivery strategies

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 172, P. 116207 - 116207

Published: Jan. 31, 2024

Lung cancer ranks among the most prevalent forms of and remains a significant factor in cancer-related mortality across world. It poses challenges to healthcare systems society as whole due its high incidence, rates, late-stage diagnosis. Resveratrol (RV), natural compound found various plants, has shown potential nanomedicine for lung treatment. RV varied effects on cells, including promoting apoptosis by increasing pro-apoptotic proteins (Bax Bak) decreasing anti-apoptotic (Bcl-2). also hinders cell proliferation influencing important signaling pathways (MAPK, mTOR, PI3K/Akt, Wnt/β-catenin) that govern progression. In addition, acts potent antioxidant, diminishing oxidative stress safeguarding cells against DNA damage. However, using alone treatment drawbacks, such low bioavailability, lack targeting ability, susceptibility degradation. contrast, nanoparticle-based delivery address these limitations hold promise improving outcomes cancer; nanoparticle formulations offer advantages improved drug delivery, increased stability, controlled release, targeted cells. This article will provide an overview cancer, explore therapeutic agent, discuss benefits highlight nanoparticles treatment, cancer. By optimizing clinical application, future studies aim enhance overall improve prognosis patients.

Language: Английский

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Glutamine addiction in tumor cell: oncogene regulation and clinical treatment

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 3, 2024

Abstract After undergoing metabolic reprogramming, tumor cells consume additional glutamine to produce amino acids, nucleotides, fatty and other substances facilitate their unlimited proliferation. As such, the metabolism of is intricately linked survival progression cancer cells. Consequently, targeting presents a promising strategy inhibit growth cell development. This review describes uptake, metabolism, transport in its pivotal role biosynthesis more. Furthermore, we have also summarized impact oncogenes like C-MYC , KRAS HIF p53 on regulation mechanisms through which triggers mTORC1 activation. In addition, different anti-cancer agents has been described prospective applications are assessed.

Language: Английский

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Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment

Cancers, Journal Year: 2024, Volume and Issue: 16(5), P. 1029 - 1029

Published: March 2, 2024

Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy often a preferred therapeutic option. Biomarker-based stratification mCRC enables use precision therapy based on individual tumor mutational profiles. Activating mutations in RAS/RAF/MAPK pathway downstream EGFR signaling have, until recently, limited EGFR-targeted therapies mCRC; however, development anti-RAS and anti-RAF together with improved strategies to limit compensatory pathways resulting survival rates several highly lethal sub-types (e.g., BRAF-mutant). The fluoropyrimidine (FP)-based regimens treat continues evolve contributing long-term survival. Future advances will need position relative made oncology.

Language: Английский

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Targeting KRAS: from metabolic regulation to cancer treatment

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 11, 2025

The Kirsten rat sarcoma viral oncogene homolog (KRAS) protein plays a key pathogenic role in oncogenesis, cancer progression, and metastasis. Numerous studies have explored the of metabolic alterations KRAS-driven cancers, providing scientific rationale for targeting metabolism treatment. development KRAS-specific inhibitors has also garnered considerable attention, partly due to challenge acquired treatment resistance. Here, we review reprogramming glucose, glutamine, lipids regulated by oncogenic KRAS, with an emphasis on recent insights into relationship between changes mechanisms driven KRAS mutant related advances targeted therapy. We focus inhibitor discovery strategies colorectal, pancreatic, non-small cell lung cancer, including current clinical trials. Therefore, this provides overview understanding associated mutation therapeutic strategies, aiming facilitate challenges support investigation strategies.

Language: Английский

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The roles of KRAS in cancer metabolism, tumor microenvironment and clinical therapy

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 13, 2025

Abstract KRAS is one of the most mutated genes, driving alternations in metabolic pathways that include enhanced nutrient uptaking, increased glycolysis, elevated glutaminolysis, and heightened synthesis fatty acids nucleotides. However, beyond mechanisms KRAS-modulated cancer metabolisms remain incompletely understood. In this review, we aim to summarize current knowledge on KRAS-related alterations cells explore prevalence significance mutation shaping tumor microenvironment influencing epigenetic modification via various molecular activities. Given rely these changes sustain cell growth survival, targeting processes may represent a promising therapeutic strategy for KRAS-driven cancers.

Language: Английский

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Digestive cancers: mechanisms, therapeutics and management

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 14, 2025

Abstract Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% annual cases cancer deaths. The etiologies, molecular features, therapeutic management these entities highly heterogeneous complex. Over last decade, genomic functional studies have provided unprecedented insights into biology cancers, identifying genetic drivers tumor progression key interaction points cells with immune system. This knowledge is continuously translated novel treatment concepts targets, which dynamically reshaping landscape tumors. In this review, we provide a concise overview etiology pathology six most common cancers system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, colorectal cancers. We comprehensively describe current stage-dependent pharmacological malignancies, chemo-, targeted, immunotherapy. For each entity, an recent advancements research progress. Finally, how heterogeneity evasion deepen our understanding therapy resistance outlook on innovative strategies that will shape future CAR-T cell therapy, antibody-drug conjugates targeted therapies.

Language: Английский

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Regulation of cellular senescence in tumor progression and therapeutic targeting: mechanisms and pathways

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: April 2, 2025

Cellular senescence, a stable state of cell cycle arrest induced by various stressors or genomic damage, is recognized as hallmark cancer. It exerts context-dependent dual role in cancer initiation and progression, functioning tumor suppressor promoter. The complexity senescence arises from its mechanistic diversity, potential reversibility, heterogeneity. A key mediator these effects the senescence-associated secretory phenotype (SASP), repertoire bioactive molecules that influence microenvironment (TME) remodeling, modulate behavior, contribute to therapeutic resistance. Given intricate biology, presents both challenges opportunities for intervention. Strategies targeting pathways, including senescence-inducing therapies senolytic approaches, offer promising avenues treatment. This review provides comprehensive analysis regulatory mechanisms governing cellular tumors. We also discuss emerging strategies highlighting novel opportunities. deeper understanding processes essential developing precision improving clinical outcomes.

Language: Английский

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Immunotherapy in Oncogene-Addicted NSCLC: Evidence and Therapeutic Approaches

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 583 - 583

Published: Jan. 11, 2025

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. The discovery specific driver mutations has revolutionized the treatment landscape oncogene-addicted NSCLC through targeted therapies, significantly improving patient outcomes. However, immune checkpoint inhibitors (ICIs) have demonstrated limited effectiveness in this context. Emerging evidence, though, reveals significant heterogeneity among different mutation subgroups, suggesting that certain subsets may benefit from ICIs, particularly when combined with other therapeutic modalities. In review, we comprehensively examine current evidence on efficacy immunotherapy NSCLC. By analyzing recent clinical trials and preclinical studies, along an overview mechanisms reduce efficacy, explored potential strategies to address these challenges, provide insights could optimize approaches integrate them effectively into algorithm for

Language: Английский

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Tumor dormancy and relapse: understanding the molecular mechanisms of cancer recurrence

Military Medical Research, Journal Year: 2025, Volume and Issue: 12(1)

Published: Feb. 11, 2025

Abstract Cancer recurrence, driven by the phenomenon of tumor dormancy, presents a formidable challenge in oncology. Dormant cancer cells have ability to evade detection and treatment, leading relapse. This review emphasizes urgent need comprehend dormancy its implications for recurrence. Despite notable advancements, significant gaps remain our understanding mechanisms underlying lack reliable biomarkers predicting provides comprehensive analysis cellular, angiogenic, immunological aspects dormancy. It highlights current therapeutic strategies targeting dormant cells, particularly combination therapies immunotherapies, which hold promise preventing By elucidating these proposing innovative research methodologies, this aims deepen ultimately facilitating development more effective recurrence improving patient outcomes.

Language: Английский

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