MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression. Among these, miR-660, located on chromosome Xp11.23, is increasingly studied for its role in cancer due to its abnormal expression in various biological contexts. It is regulated by 8 competing endogenous RNAs (ceRNAs), which adds complexity to its function. miR- 660 targets 19 genes involved in 6 pathways such as PI3K/AKT/mTOR, STAT3, Wnt/β-catenin, p53, NF‑κB, and RAS, influencing cell cycle, proliferation, apoptosis, and invasion/migration. It also plays a role in resistance to chemotherapies like cisplatin, gemcitabine, and sorafenib in lung adenocarcinoma (LUAD), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC), thus highlighting its clinical importance. Additionally, leveraging liposomes as nanocarriers presents a promising avenue for enhancing cancer drug delivery. Our comprehensive study not only elucidates the aberrant expression patterns, biological functions, and regulatory networks of miR-660 and its ceRNAs but also delves into the intricate signaling pathways implicated. We envisage that our findings will furnish a robust framework and serve as a seminal reference for future investigations of miR-660, fostering advancements in cancer research and potentially catalyzing breakthroughs in cancer diagnosis and treatment paradigms.

This review examines the prevalence, molecular mechanisms, and clinical implications of RAS mutations in Central Nervous System (CNS) tumors, with a particular focus on glioblastoma. We summarize the current understanding of RAS-driven oncogenic pathways, their contribution to tumor progression, and potential therapeutic strategies targeting RAS and its downstream effectors. Although direct RAS mutations are rare in primary CNS tumors, alterations in RAS signaling, such as NF-1 loss and aberrant receptor tyrosine kinase activation, contribute to malignant progression. Furthermore, emerging evidence links RAS mutations to brain metastases, highlighting their significance in CNS oncology. We also discuss recent clinical trials investigating RAS-targeted therapies, including covalent inhibitors, MEK inhibitors, and novel combination approaches. Given the increasing recognition of RAS pathway alterations in CNS malignancies, further research is needed to elucidate their role in tumor biology and explore targeted therapeutic interventions.

Endometrial cancer (EC) is a prevalent gynecological malignancy with a complex molecular landscape, contributing to significant global morbidity and mortality. Dysregulated signaling pathways such as PI3K/AKT/mTOR and RAS/RAF/MEK drive EC progression by promoting uncontrolled cell proliferation, survival, angiogenesis, and metastasis. Mutations in genes like PTEN and PIK3CA further underpin tumor aggressiveness. Molecular alterations in these pathways not only serve as biomarkers for prognosis but also guide the formulation of targeted therapies, such as mTOR inhibitors and anti-angiogenic agents. While such therapies show promise, optimizing their efficacy and minimizing adverse effects requires further research. A comprehensive approach integrating early detection (e.g., addressing postmenopausal bleeding), preventive strategies (e.g., managing obesity), increasing diagnostic sensitivity (e.g., transvaginal ultrasound) and advanced molecularly tailored treatments (e.g., AI & ML) is critical to reducing the burden of this disease. By targeting key signaling pathways, leveraging AI-driven methodologies, and addressing treatment resistance, we can enhance patient outcomes, also mitigate the rising global impact of EC.

RAS mutations occur in about 30% of human cancers, leading to enhanced RAS signaling and tumor growth. KRAS is the most commonly mutated oncogene in human tumors, especially lung, pancreatic, and colorectal cancers. Direct targeting of KRAS is difficult due to its highly conserved sequence; but, its complex with the guanine nucleotide exchange factor Son of Sevenless (SOS) 1 promises an attractive target for inhibiting RAS-mediated signaling. Here, we first revealed putative allosteric binding sites of the SOS1, KRASG12C-SOS1 complex, and the ternary KRASG13D-SOS1 complex structures using two network-based models, the essential site scanning analysis and the residue interaction network model. The results enabled us to identify two new putative allosteric pockets for the ternary KRASG13D-SOS1 complex. These were then screened together with the known ligand binding site against the natural compounds in the InterBioScreen (IBS) database using the Glide software package developed by Schrödinger, Inc. The docking poses of seven hit compounds were assessed using 400 ns long molecular dynamics (MD) simulations with two independent replicas using Desmond, coupled with thermal MM-GBSA calculations for the estimation of the binding free energy values. The structural skeleton of the seven proposed compounds consists of different functional groups and heterocyclic rings that possess anti-cancer activity and exhibit persistent interactions with key residues in binding pockets throughout the MD simulations. STOCK1N-09823 was determined as the most promising hit that promoted the disruption of the interactions R73 (chain A)/N879 and R73 (chain A)/Y884, which are key for SOS1-mediated KRAS activation.

Despite epidemiological data on anaemia being available on a global scale, the prevalence of anaemia in the UK is not well described.

To describe anaemia prevalence and testing patterns for haemoglobin and other blood parameters.

This study was a descriptive population-based cohort study using data drawn from the Clinical Practice Research Datalink Aurum database in 2019.

Demographic data were extracted for each person who was registered at their current practice during 2019, including linked data on Index of Multiple Deprivation. Anaemia prevalence in 2019 was calculated based on World Health Organization-specified age and gender thresholds for haemoglobin. Anaemia was classified based on mean corpuscular volume and ferritin. People with anaemia were followed up for up to 1 year to investigate longitudinal testing patterns for haemoglobin.

The cohort contained 14 million people. Anaemia prevalence in England in 2019 was 4.1% (583 847/14 207 841) (5.1% [363 438/7 121 614] females and 3.1% [220 409/7 086 227] males). Prevalence was higher in people aged >65 years, people of Black and Asian ethnicities, and people living in areas with higher social deprivation. Only half of people with anaemia and a mean corpuscular volume of ≤100 fL had an accompanying ferritin value recorded. About half of people with anaemia had a follow-up haemoglobin test within 1 year, most of which still indicated anaemia.

Anaemia is prevalent in the UK with large disparities between levels of demographic variables. Investigation and follow-up of anaemia is suboptimal in many patients. Health interventions aimed at improving anaemia investigation and treatment are needed, particularly in the most at-risk groups.

Acute myeloid leukaemia (AML) is a hard to treat blood cancer. Mutations in FLT3 are common among the genetic aberrations that characterise the cancer. Patients initially react to FLT3 inhibitors but drug resistance is a hinder to successful therapy. To better understand the mechanisms leading to drug resistance, we generated four AML cell lines resistant to the inhibitors gilteritinib or FF-10101, and explored their resistance mechanisms. We further tested whether the novel inhibitor Chen-9u could be used to limit cell growth. The results showed that each of the four resistant cell lines became resistant through a different mechanism. Resistant cells showed decreased FLT3 and increased NRAS pathway activity and reduced DNA synthesis due to decrease in CDK4 activity. Resistance mechanisms included resistance mutations in FLT3 (C695F and N701K), and a novel mutation in NRAS (G12C). In a fourth line, resistance might have developed through a MYCN mutation. Cell growth was inhibited by Chen-9u and resistant clones could not be obtained with this inhibitor. The results highlight opportunities and limitations. On the one hand, resistant cells were produced due to different mechanisms, showing the versatility of tumour cells. Furthermore, resistance developed to the most advanced inhibitors, one of which is covalent and the other non-covalent but highly specific. On the other hand, it is shown that DNA synthesis is reduced, which means that resistance has evolutionary consequences. Finally, the novel drug-resistant cell lines may serve as useful models for better understanding of the cellular events associated with inherent and acquired drug resistance.

Precision medicine has revolutionized the treatment of colorectal cancer by enabling a personalized approach tailored to each patient's unique genetic characteristics. Genomic profiling allows for the identification of specific mutations in genes such as KRAS, BRAF, and PIK3CA, which play a crucial role in cell signaling pathways that regulate cell proliferation, apoptosis, and differentiation. This information enables doctors to select targeted therapies that inhibit specific molecular pathways, maximizing treatment effectiveness and minimizing side effects. Precision medicine also facilitates adaptive monitoring of tumor progression, allowing for adjustments in therapy to maintain treatment effectiveness. While challenges such as high costs, limited access to genomic technology, and the need for more representative genomic data for diverse populations remain, collaboration between researchers, medical practitioners, policymakers, and the pharmaceutical industry is crucial to ensure that precision medicine becomes a standard of care accessible to all. With continued advances and support, precision medicine has the potential to improve treatment outcomes, reduce morbidity and mortality rates, and enhance the quality of life for colorectal cancer patients worldwide.

Ras has traditionally been regarded as a positive regulator and therapeutic target due to its role in cell proliferation, but recent findings indicate a more nuanced role in cell migration, where suppressed Ras activity can unexpectedly promote migration. To clarify this complexity, we systematically modulate Ras activity using various RasGEF and RasGAP proteins and assess their effects on migration dynamics. Leveraging optogenetics, we assess the immediate, non-transcriptional effects of Ras signaling on migration. Local RasGEF recruitment to the plasma membrane induces protrusions and new fronts to effectively guide migration, even in the absence of GPCR/G-protein signaling whereas global recruitment causes immediate cell spreading halting cell migration. Local RasGAP recruitment suppresses protrusions, generates new backs, and repels cells whereas global relocation either eliminates all protrusions to inhibit migration or preserves a single protrusion to maintain polarity. Consistent local and global increases or decreases in signal transduction and cytoskeletal activities accompany these morphological changes. Additionally, we performed cortical tension measurements and found that RasGEFs generally increase cortical tension while RasGAPs decrease it. Our results reveal a biphasic relationship between Ras activity and cellular dynamics, reinforcing our previous findings that optimal Ras activity and cortical tension are critical for efficient migration.

This study challenges the traditional view of Ras as solely a positive regulator of cell functions by controlling of gene expression. Using optogenetics to rapidly modulate Ras activity in Dictyostelium , we demonstrate a biphasic relationship between Ras activity and migration: both excessive and insufficient Ras activity impair cell movement. Importantly, these effects occur rapidly, independent of transcriptional changes, revealing the mechanism by which Ras controls cell migration. The findings suggest that optimal Ras activity and cortical tension are crucial for efficient migration, and that targeting Ras in cancer therapy should consider the cell's initial state, aiming to push Ras activity outside the optimal range for migration. This nuanced understanding of the role of Ras in migration has significant implications for developing more effective cancer treatments, as simply inhibiting Ras might inadvertently promote metastasis in certain contexts.

Ras proteins are pivotal in the regulation of cell proliferation signals, and their dysregulation is intricately linked to the pathogenesis of various malignancies. Peptide inhibitors hold distinct advantages in targeting Ras proteins, attributable to their extensive binding domains, which result from the smooth surfaces of the proteins. The array of specific strategies includes the employment of full hydrocarbon chains, cyclic peptides, linear peptides, and N-terminal nucleation polypeptides. These methods effectively suppress the Ras signaling pathway through distinct mechanisms, highlighting their potential as anti-neoplastic agents. Moreover, cutting-edge methodologies, including the N-terminal aspartate nucleation strategy and the utilization of hydrocarbon-stapled peptides, are transforming the landscape of therapeutics aimed at Ras proteins. These innovations highlight the promise of peptide libraries and combinatorial chemistry in augmenting binding affinity, specificity, and cellular permeability, which are pivotal for the development of potent anti-cancer agents. The incorporation of dual therapeutic strategies, such as the synergy between peptide inhibitors and conventional chemotherapy or the use of radiotherapy enhancers, emerges as a compelling strategy to bolster the efficacy of cancer treatments targeting the Ras-MAPK pathway. Furthermore, recent studies have demonstrated that Ras-targeting stabilized peptides can amplify the radio-sensitivity of cancer cells, offering an innovative approach to enhance the efficacy of radiation therapy within cancer management.

RAS proteins, as pivotal signal transduction molecules, are frequently mutated and hyperactivated in various human cancers, closely associated with tumor cell proliferation, survival, and metastasis. Despite extensive research on RAS targeted therapies, developing effective RAS inhibitors remains a significant challenge. Natural products, endowed with unique chemical structures and diverse biological activities through long-term natural selection, have emerged as a vital resource for discovering novel RAS-targeted therapeutic drugs. This review focuses on the latest advancements in targeting RAS with natural products and categorizes these natural products based on their mechanisms of action. Additionally, we discuss the challenges faced by these natural products during clinical translation, including issues related to pharmacokinetics. Strategies such as combination therapy, structural optimization, and drug delivery systems are anticipated to enhance efficacy and overcome these challenges.

Small-molecule compounds that even partially restore the GTPase activity of RASG12V can be used in anticancer therapy. Until now, attempts to obtain such compounds have failed. Compounds with this ability have been defined in our research.

The compounds were initially identified through virtual screening, and their optimal binding conformation in the RAS SW-II pocket was determined using the flexible docking technique. Efficacy was verified based on the IC50 determination, GTPase activity, as well as the AKT and ERK phospho WB assays.

The IC50 of the tested compounds was significantly lower against cells with the RASG12V mutation than against selected types of normal cells. The molecular mechanism of action of these compounds was proposed - minimization of the negative impact of the V12 sidechain on GTP hydrolysis of RASG12V. The work also indicates that the model of action of RAS mutants in cell lines is incomplete. The analysed cell line (SW-480) with RAS mutations does not always show increased ERK and AKT activity.

We have demonstrated molecules that partially restore the GTPase activity of RASG12V. Their mechanism of action is well explained based on current RAS mutant conformation and mechanistic models. These molecules inhibit the RAS-AKT pathway and show higher cytotoxicity against cancer cells with the RASG12V mutation (SW-480 cell line). However, SW-480 cells can switch into the subline proliferating independently of AKT phosphorylation and show partial resistance to the molecules described in this article.

Acute myeloid leukemias (AMLs) comprise a group of genetically heterogeneous hematological malignancies that result in the abnormal growth of leukemic cells and halt the maturation process of normal hematopoietic stem cells. Despite using molecular and cytogenetic risk classification to guide treatment decisions, most AML patients survive for less than five years. A deeper comprehension of the disease's biology and the use of new, targeted therapy approaches could potentially increase cure rates. RAS oncogene mutations are common in AML patients, being observed in about 15-20% of AML cases. Despite extensive efforts to find targeted therapy for RAS-mutated AMLs, no effective and tolerable RAS inhibitor has received approval for use against AMLs. The frequency of RAS mutations increases in the context of AMLs' chemoresistance; thus, novel anti-RAS strategies to overcome drug resistance and improve patients' therapy responses and overall survival are the need of the hour. In this article, we aim to update the current knowledge on the role of RAS mutations and anti-RAS strategies in AML treatments.

The study is to evaluate the efficacy and safety of combined anlotinib and EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) who had gradual, oligo, or potential progression after previous EGFR-TKIs treatment.

We conducted an open-label, single-arm, multicenter, phase II trial in China. Eligible patients were 18-75 years old with histologically or cytologically confirmed NSCLC who were EGFR mutation positive and showed gradual, oligo, or potential progression after EGFR-TKIs. Anlotinib (12 mg/day) was administered orally for 2 weeks and then off 1 week in a 3-week cycle. EGFR-TKIs were continue used. The primary endpoint was progression-free survival (PFS). The secondary endpoints included 6- and 12-month PFS rate, objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety.

From July 2019 to December 2022, 120 patients were enrolled. The median PFS (mPFS) was 9.1 months (95% CI 6.8-11.7). The PFS rates at 6 and 12 months was 68.5% and 38.8% respectively. For 86 patients with first-line 1st /2nd generation EGFR-TKIs, the mPFS was 9.2 months (95% CI 6.7-12.6). For 32 patients with first-line 3rd generation EGFR-TKIs, the mPFS was 10.3 months (95% CI 6.1-13.3). Overall ORR and DCR were 6.7% (95% CI 2.9-12.7) and 87.5% (95% CI 80.2-92.8), respectively. 52.5% of patients had grade 3 or higher treatment-emergent adverse events (TEAEs).

Anlotinib in combination with continuation of EGFR-TKIs prolonged the clinical benefit of EGFR-TKIs, demonstrating favorable survival outcomes and manageable toxicity in NSCLC treated with EGFR-TKIs and had specific progression modes, such as gradual progression.

NCT04007835.

RAS mutations are prevalent in leukemia, including mutations at G12, G13, T58, Q61, K117, and A146. These mutations are often crucial for tumor initiation, maintenance, and recurrence. Although much is known about RAS function in the last 40 years, a substantial knowledge gap remains in understanding the mutation-specific biological activities of RAS in cancer and the approaches needed to target specific RAS mutants effectively. The recent approval of KRASG12C inhibitors, adagrasib and sotorasib, has validated KRAS as a direct therapeutic target and demonstrated the feasibility of selectively targeting specific RAS mutants. Nevertheless, KRASG12C remains the only RAS mutant successfully targeted with FDA-approved inhibitors for cancer treatment in patients, limiting its applicability for other oncogenic RAS mutants, such as G12D, in leukemia. Despite these challenges, new approaches have generated optimism about targeting specific RAS mutations in an allele-dependent manner for cancer therapy, supported by compelling biochemical and structural evidence, which inspires further exploration of RAS allele-specific vulnerabilities. This review will discuss the recent advances and challenges in the development of therapies targeting RAS signaling, highlight emerging therapeutic strategies, and emphasize the importance of allele-specific approaches for leukemia treatment.

Rhabdomyosarcoma risk stratification is traditionally determined by tumor histology and staging. Recent studies revealed the importance of molecular features in predicting prognosis. We investigated prognosis by age of onset and mutation incidence in rhabdomyosarcoma tumors.

We retrospectively extracted clinical and genomic data from the Clinomics dataset (n = 641). Inclusion criteria was tumors with at least one gene mutation with >5% mutation incidence. Exclusion criteria were unknown risk stratification and age of onset. Statistical analysis was performed using ANOVA (p < 0.05) and Tukey's HSD to compare mutation incidence, EFS, and OS among age groups.

Among 641 patients with rhabdomyosarcoma, 8 of 39 screened genes had >5% mutation incidence: NRAS, BCOR, NF1, TP53, FGFR4, KRAS, HRAS, and CTNNB1. The final cohort consisted of 370 patients: 51 (Age: 0-2 Years), 140 (Age: 2-5 Years), 112 (Age: 5-12 Years) and 67 (Age: 12+). Later age of onset is associated with higher incidence of BCOR and HRAS mutations (p < 0.005, p < 0.001) and poorer EFS and OS (p < 0.05, p < 0.001). In patients with BCOR mutations, later age of onset is associated with poorer EFS and OS (p < 0.005, p < 0.001). NF1 mutations are equally distributed among age groups (p = 0.82), but later age of onset is associated with poorer EFS and OS (p < 0.005, p < 0.001).

In patients with at least one mutation in BCOR, NF1, TP53, KRAS, HRAS, or CTNNB1, later age of onset is associated with poorer prognosis. In patients with mutations only in tumor suppressor genes BCOR or NF1, later age of onset is associated with poorer prognosis.

Retrospective Cohort Study.

II.

Misshapen/NIKs-related kinase (MINK) 1 belongs to the mammalian germinal center kinase (GCK) family. It contains the N-terminal, conserved kinase domain, a coiled-coil region, a proline-rich region, and a GCK, C-terminal domain with the Citron-NIK-Homology (CNH) domain. The kinase is an essential component of cellular signaling pathways, which include Wnt signaling, JNK signaling, pathways engaging Ras proteins, the Hippo pathway, and STRIPAK complexes. It thus contributes to regulating the cell cycle, apoptosis, cytoskeleton organization, cell migration, embryogenesis, or tissue homeostasis. MINK1 plays an important role in immunological responses, inhibiting Th17 and Th1 cell differentiation and regulating NLRP3 inflammasome function. It may be considered a link between ROS and the immunological system, and a potential antiviral target for human enteroviruses. The kinase has been implicated in the pathogenesis of sepsis, rheumatoid arthritis, asthma, SLE, and more. It is also involved in tumorigenesis and drug resistance in cancer. Silencing MINK1 reduces cancer cell migration, suggesting potential for new therapeutic approaches. Targeting MINK1 could be a promising treatment strategy for patients insensitive to current chemotherapies, and could improve their prognosis. Moreover, MINK1 plays an important role in the nervous system and the cardiovascular system development and function. The modulation of MINK1 activity could influence the course of neurodegenerative diseases, including Alzheimer's disease. Further exploration of the activity of the kinase could also help in gaining more insight into factors involved in thrombosis or congenital heart disease. This review aims to summarize the current knowledge on MINK1, highlight its therapeutic and prognostic potential, and encourage more studies in this area.

SOS1 is a crucial guanine nucleotide exchange factor for KRAS. It facilitates the transition of KRAS from inactive GDP-bound state to active GTP-bound state. The activation of KRAS triggers downstream signaling pathways, promoting tumor initiation and progression. Inhibiting SOS1 to prevent KRAS activation is an effective strategy for treating tumors driven by KRAS.

This review identified patents claiming to be SOS1 inhibitors or SOS1-KRAS interaction modulators published between January 2022 and June 2024 using Cortellis Drug Discovery Intelligence. A total of 15 patent applications from 5 different applicants were assessed.

In KRAS-driven tumors, inhibiting SOS1 significantly affect cell proliferation and migration by modulating the RAS/MAPK and PI3K/AKT/mTOR signaling pathways. Since 2022, numerous patents for SOS1 inhibitors have been published. The majority of SOS1 inhibitors are currently in the preclinical phase of development, with only a few progressing to clinical trials. However, these inhibitors face significant challenges in clinical studies, including limited efficacy of monotherapies, safety concerns, and the necessity to enhance PK properties. Despite their excellent in vitro performance, SOS1 inhibitors must address issues related to safety, pharmacokinetics, and pharmacodynamics in clinical applications.

Necroptosis is an innovative class of programmed autophagy (Atg) and necrosis; considered as a type of homeostatic housekeeping machinery that have observed an escalating concern due to its power in alleviating Cisplatinum-induced nephrotoxicity. This article elucidated in details the prospective role of both autophagy and necroptosis on Cisplatinum-triggered nephrotoxicity and investigating more potent therapy via lactoferrin and Ti-NPS conjugation. Cisplatinum is a commonly used chemotherapeutic drug; one of the limiting adverse actions of cisplatinum is renal toxicity. Upon cisplatinum administration, autophagy is highly stimulated in the kidney to shield against nephrotoxicity. Atg is a lysosomal degradation process which discards detorirated proteins to retain cell homeostasis. This article summarizes necroptosis progress in reconizing cisplatinum nephrotoxicity and debates how this progress can help in discovering more potent therapy via lactoferrin and Ti-NPS conjugation via monitoring autophagy and apoptotic biomarkers X-box-binding protein 1 (XBP), C/EBP homologous protein (CHOP), hypoxanthine phosphoribosyltransferase-1 (HPRT), FKBP prolyl isomerase 1B (FKBP), Cellular myelocytomatosis oncogene (C-myc), tumor suppressor gene (P53) and tumor necrosis factor (TNF-α). Cisplatinum nephrotoxicity was conducted in rat model via an oral dose of (2 mg/kg BW) for one month furthermore a comparative study was conducted among TiNPs-loaded Cisplatinum and Lactoferrin loaded Cisplatinum. Loaded drug delivery system counteracted Cisplatinum triggered nephrotoxicity via controlling autophagy and apoptotic XBP, CHOP, HPRT, FKBP, C-myc, P53 and TNF-α signaling pathway.

Activating mutations in NRAS account for 15-20% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations.

Variants in the RAS family (HRAS, NRAS and KRAS) are among the most common mutations found in cancer. About 19% patients with cancer harbor RAS mutations, which are typically associated with poor clinical outcomes. Over the past four decades, KRAS has long been considered an undruggable target due to the absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements in drug design have made RAS-targeting therapies viable, particularly with the approval of direct KRASG12C inhibitors, such as sotorasib and adagrasib, for treating non-small cell lung cancer (NSCLC) with KRASG12C mutations. Other KRAS-mutant inhibitors targeting KRASG12D are currently being developed for use in the clinic, particularly for treating highly refractory malignancies like pancreatic cancer. Herein, we provide an overview of RAS signaling, further detailing the roles of the RAS signaling pathway in carcinogenesis. This includes a summary of RAS mutations in human cancers and an emphasis on therapeutic approaches, as well as de novo, acquired, and adaptive resistance in various malignancies.

Paeoniflorin (Pae) can improve diabetes mellitus (DM), especially endothelial dysfunction induced by high glucose (HG). Molecularly, the mechanism pertinent to Pae and DM lacks further in-depth research. Hence, this study determined the molecular mechanism of Pae in treating DM through network pharmacology. The target of Pae was analyzed by TCMSP database, and DM-related genes were dissected by Genecards database and Omim database. PPI network was constructed for cross targets through Cytoscape 3.9.1 and STRING platform. GO and KEGG analyses were carried out on the cross targets. Protein molecular docking verification was completed by AutoDockTools and Pymol programs. Human umbilical vein endothelial cells (HUVECs) were separately treated with HG, Pae (5, 10, 20 μM) and/or HRAS overexpression plasmids (oe-HRAS). The cell viability, apoptosis and the protein expressions of HRAS and Ras-GTP were evaluated. There were 50 cross targets between Pae and DM, and VEGFA, EGFR, HRAS, SRC and HSP90AA1 were the key genes identified by PPI network analysis. GO and KEGG analyses revealed signal paths such as Rap1 and Ras. Molecular docking results confirmed that Pae had a good binding ability with key genes. In HG-treated HUVECs, Pae dose-dependently facilitated cell viability, attenuated cell apoptosis, and dwindled the expressions of HRAS and Ras-GTP, but these effects of Pae were reversed by oe-HRAS. In conclusion, Pae regulates the viability and apoptosis of HG-treated HUVECs by inhibiting the expression of HRAS.

Lung enteric-type adenocarcinoma (ETAC) is a rare subtype of non-small cell lung cancer (NSCLC), comprising approximately 0.6% of all primary lung adenocarcinomas. It is characterized by a tendency for early metastasis and a prognosis comparable to that of common lung adenocarcinoma. This case report described a patient with lung-ETAC who developed gastric metastasis. The patient underwent treatment with chemotherapy and a PD-1 inhibitor, resulting in disease remission with a progression-free survival (PFS) of 8 months. The follow-up time was 13 months. This case report was aimed to enhance understanding of the biological behavior of this rare tumor and provide insights into potential future treatment strategies.

The histone-lysine N-methyltransferase SMYD1, which is specific to striated muscle, plays a crucial role in regulating early heart development. Its deficiency has been linked to the occurrence of congenital heart disease. Nevertheless, the precise mechanism by which SMYD1 deficiency contributes to congenital heart disease remains unclear.

We established a SMYD1 knockout pluripotent stem cell line and a doxycycline-inducible SMYD1 expression pluripotent stem cell line to investigate the functions of SMYD1 utilizing an in vitro-directed myocardial differentiation model.

Cardiomyocytes lacking SMYD1 displayed drastically diminished differentiation efficiency, concomitant with heightened proliferation capacity of cardiac progenitor cells during the early cardiac differentiation stage. These cellular phenotypes were confirmed through experiments inducing the re-expression of SMYD1. Transcriptome sequencing and small molecule inhibitor intervention suggested that the GSK3β/β-catenin&ERK signaling pathway was involved in the proliferation of cardiac progenitor cells. Chromatin immunoprecipitation demonstrated that SMYD1 acted as a transcriptional activator of GSK3β through histone H3 lysine 4 trimethylation. Additionally, dual-luciferase analyses indicated that SMYD1 could interact with the promoter region of GSK3β, thereby augmenting its transcriptional activity. Moreover, administering insulin and Insulin-like growth factor 1 can enhance the efficacy of myocardial differentiation in SMYD1 knockout cells.

Our research indicated that the participation of SMYD1 in the GSK3β/β-catenin&ERK signaling cascade modulated the proliferation of cardiac progenitor cells during myocardial differentiation. This process was partly reliant on the transcription of GSK3β. Our research provided a novel insight into the genetic modification effect of SMYD1 during early myocardial differentiation. The findings were essential to the molecular mechanism and potential interventions for congenital heart disease.

The discovery of KRAS mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: "sotorasib", "adagrasib", "divarasib" and "KRAS G12C inhibitors." The last search was on 5 June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease.

The purpose of this study was to investigate the effects of BOC on glioblastoma cells and its underlying mechanisms. In vitro, BOC-knockdown was performed in glioma cell lines. CCK-8 and Transwell were used to assess the impact of BOC on the viability, invasion, and migration of gliobma cells. RNA-seq technology was employed to analyze the differential gene expression between BOC-knockdown glioma cells and the control group, and qRT-PCR was used to validate the expression of downstream differential genes. SMO-overexpression was performed to investigate the effects of SMO on glioma cells. A BOC-knockdown mouse subcutaneous tumor model was to verify the effects of BOC on mouse tumors. Tissue microarray technology was used to detect the expression of BOC and SMO in samples of normal human brain tissue and glioma tissue. In vitro, BOC-knockdown inhibited the viability, invasion, and migration of glioma cells, as well as downregulated the expression of downstream differential genes SMO, EGFR, HRAS, and MRAS. Conversely, SMO-overexpression upregulated the viability, invasion, and migration abilities of BOC-knockdown cells. In vivo, BOC-knockdown suppressed tumor growth in mice and downregulated the expression of downstream differential genes SMO, EGFR, HRAS, and MRAS. Tissue microarray results showed that both BOC and SMO were highly expressed in glioma tissues. BOC is aberrantly overexpressed in glioma patients and promotes glioma development. Mechanistically, BOC activates the Hedgehog (Hh) and RAS signaling pathways by upregulating the expression of SMO, EGFR, HRAS, and MRAS, thereby facilitating the Proliferation, invasion and migration of glioma cells.

Understanding the state transitions in biological systems and identifying critical steady states are crucial for investigating disease development and discovering key therapeutic targets. To advance the study of state transitions in specific biological entities, we proposed the Ternary Entity State Inference System (T-ESIS). T-ESIS builds upon the Entity State Inference System by providing richer information on entity states, where states can take values of 0, 1, or 1/2, representing activation, inhibition, and normal states, respectively. This method infers state transition pathways based on interaction relationships and visualizes them through the Entity State Network. Furthermore, the cyclic structures within the Entity State Network capture positive and negative feedback loops, providing a topological foundation for the formation of steady states. To demonstrate the applicability of T-ESIS, entity states were modeled, and attractor analysis was conducted in non-small cell lung cancer (NSCLC) networks. Our analysis provided valuable insights into targeted therapy for NSCLC, highlighting the potential of T-ESIS in uncovering therapeutic targets and understanding disease mechanisms. Moreover, the proposed T-ESIS framework facilitated the inference of entity state transitions and the analysis of steady states in biological systems, offering a novel approach for studying the dynamic principles of these systems. This ternary dynamic modeling approach not only deepened our understanding of biological networks but also provided a methodological reference for future research in the field.

To explore the pharmacodynamic ingredients and pharmacologic mechanism of Haizao Yuhu Decoction (HYD) in treating hyperthyroidism via an analysis integrating network pharmacology, molecular docking, and non-targeted serum metabolomics.

Therapeutic targets of hyperthyroidism were searched through multi-array analyses in the Gene Expression Omnibus (GEO) database. Hub genes were subjected to the construction of a protein-protein interaction (PPI) network, and GO and KEGG enrichment analyses. Targets of active pharmaceutical ingredients (APIs) in HYD and those of hyperthyroidism were intersected to yield hub genes, followed by validations via molecular docking and non-targeted serum metabolomics.

112 hub genes were identified by intersecting APIs of HYD and therapeutic targets of hyperthyroidism. Using ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) in both negative and positive ion polarity modes, 279 compounds of HYD absorbed in the plasma were fingerprinted. Through summarizing data yielded from network pharmacology and non-targeted serum metabolomics, 214 common targets were identified from compounds of HYD absorbed in the plasma and therapeutic targets of hyperthyroidism, including PTPN11, PIK3CD, EGFR, HRAS, PIK3CA, AKT1, SRC, PIK3CB, and PIK3R1. They were mainly enriched in the biological processes of positive regulation of gene expression, positive regulation of MAPK cascade, signal transduction, protein phosphorylation, negative regulation of apoptotic process, positive regulation of protein kinase B signaling and positive regulation of MAP kinase activity; and molecular functions of identical protein binding, protein serine/threonine/tyrosine kinase activity, protein kinase activity, RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding and protein binding. A total of 185 signaling pathways enriched in the 214 common targets were associated with cell proliferation and angiogenesis.

HYD exerts a pharmacological effect on hyperthyroidism via inhibiting pathological angiogenesis in the thyroid and rebalancing immunity.

In the setting of pediatric and adolescent young adult cancer, increased access to genomic profiling has enhanced the detection of genetic variation associated with cancer predisposition, including germline syndromic conditions. Noonan syndrome (NS) is associated with the germline RAS pathway activating alterations and increased risk of cancer. Herein, we describe our comprehensive molecular profiling approach, the association of NS with glioma and glioneuronal tumors, and the clinical and histopathologic characteristics associated with the disease.

Within an institutional pediatric cancer cohort (n = 314), molecular profiling comprised of paired somatic disease-germline comparator exome analysis, RNA sequencing, and tumor classification by DNA methylation analysis was performed.

Through the implementation of paired analysis, this study identified 4 of 314 (1.3%) individuals who harbored a germline PTPN11 variant associated with NS, of which 3 individuals were diagnosed with a glioma or glioneuronal tumor. Furthermore, we extend this study through collaboration with a peer institution to identify two additional individuals with NS and a glioma or glioneuronal tumor. Notably, in three of five (60%) individuals, paired genomic profiling led to a previously unrecognized diagnosis of Noonan syndrome despite an average age of cancer diagnosis of 16.8 years. The study of the disease-involved tissue identified signaling pathway dysregulation through somatic alteration of genes involved in cellular proliferation, survival, and differentiation.

Comparative pathologic findings are presented to enable an in-depth examination of disease characteristics. This comprehensive analysis highlights the association of gliomas and glioneuronal tumors with RASopathies and the potential therapeutic challenges and importantly demonstrates the utility of genomic profiling for the identification of germline cancer predisposition.

In the clinical development of farnesyltransferase inhibitors (FTIs) for HRAS-mutant tumors, responses varied by cancer type. Co-occurring mutations may affect responses. We aimed to uncover cooperative genetic events specific to HRAS-mutant tumors and to study their effect on sensitivity to FTIs. Using targeted sequencing data from the MSK-IMPACT and Dana-Farber Cancer Institute Genomic Evidence Neoplasia Information Exchange databases, we identified comutations that were observed predominantly in HRAS-mutant versus KRAS-mutant or NRAS-mutant cancers. HRAS-mutant cancers had a higher frequency of coaltered mutations (48.8%) in the MAPK, PI3K, or RTK pathway genes, compared with KRAS-mutant (41.4%) and NRAS-mutant (38.4%) cancers (p < 0.05). Class 3 BRAF, NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS-mutant lineages. To study the effects of comutations on sensitivity to FTIs, HrasG13R was transfected into "RASless" (Kraslox/lox/Hras-/-/Nras-/-/RERTert/ert) mouse embryonic fibroblasts (MEFs), which sensitized nontransfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion and Pik3caH1047R transduction led to resistance to tipifarnib in HrasG13R-transfected MEFs in the presence or absence of KrasWT, whereas BrafG466E transduction led to resistance to tipifarnib only in the presence of KrasWT. Combined treatment with tipifarnib and MEK inhibition sensitized cells to tipifarnib in all settings, including in MEFs with PI3K pathway comutations. HRAS-mutant tumors demonstrate lineage-dependent MAPK or PI3K pathway alterations, which confer resistance to tipifarnib. The combined use of FTIs and MEK inhibition is a promising strategy for HRAS-mutant tumors.

Advancements in our comprehension of tumor biology and chemoresistance have spurred the development of treatments that precisely target specific molecules within the body. Despite the expanding landscape of therapeutic options, there persists a demand for innovative approaches to address unmet clinical needs. RNA therapeutics have emerged as a promising frontier in this realm, offering novel avenues for intervention such as RNA interference and the utilization of antisense oligonucleotides (ASOs). ASOs represent a versatile class of therapeutics capable of selectively targeting messenger RNAs (mRNAs) and silencing disease-associated proteins, thereby disrupting pathogenic processes at the molecular level. Recent advancements in chemical modification and carrier molecule design have significantly enhanced the stability, biodistribution, and intracellular uptake of ASOs, thereby bolstering their therapeutic potential. While ASO therapy holds promise across various disease domains, including oncology, coronary angioplasty, neurological disorders, viral, and parasitic diseases, our review manuscript focuses specifically on the application of ASOs in targeted cancer therapies. Through a comprehensive examination of the latest research findings and clinical developments, we delve into the intricacies of ASO-based approaches to cancer treatment, shedding light on their mechanisms of action, therapeutic efficacy, and prospects.

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

The factors driving glioma progression remain poorly understood. Here, the epigenetic regulator TRIM24 is identified as a driver of glioma progression, where TRIM24 overexpression promotes HRasV12 anaplastic astrocytoma (AA) progression into epithelioid GBM (Ep-GBM)-like tumors. Co-transfection of TRIM24 with HRasV12 also induces Ep-GBM-like transformation of human neural stem cells (hNSCs) with tumor protein p53 gene (TP53) knockdown. Furthermore, TRIM24 is highly expressed in clinical Ep-GBM specimens. Using single-cell RNA-sequencing (scRNA-Seq), the authors show that TRIM24 overexpression impacts both intratumoral heterogeneity and the tumor microenvironment. Mechanically, HRasV12 activates phosphorylated adaptor for RNA export (PHAX) and upregulates U3 small nucleolar RNAs (U3 snoRNAs) to recruit Ku-dependent DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Overexpressed TRIM24 is also recruited by PHAX to U3 snoRNAs, thereby facilitating DNA-PKcs phosphorylation of TRIM24 at S767/768 residues. Phosphorylated TRIM24 induces epigenome and transcription factor network reprogramming and promotes Ep-GBM-like transformation. Targeting DNA-PKcs with the small molecule inhibitor NU7441 synergizes with temozolomide to reduce Ep-GBM tumorigenicity and prolong animal survival. These findings provide new insights into the epigenetic regulation of Ep-GBM-like transformation and suggest a potential therapeutic strategy for patients with Ep-GBM.

The ubiquitously expressed small GTPase Ras-related protein 1B (RAP1B) acts as a molecular switch that regulates cell signaling, cytoskeletal remodeling, and cell trafficking and activates integrins in platelets and lymphocytes. The residue G12 in the P-loop is required for the RAP1B-GTPase conformational switch. Heterozygous germline RAP1B variants have been described in patients with syndromic thrombocytopenia. However, the causality and pathophysiological impact remained unexplored. We report a boy with neonatal thrombocytopenia, combined immunodeficiency, neutropenia, and monocytopenia caused by a heterozygous de novo single nucleotide substitution, c.35G>A (p.G12E) in RAP1B. We demonstrate that G12E and the previously described G12V and G60R were gain-of-function variants that increased RAP1B activation, talin recruitment, and integrin activation, thereby modifying late responses such as platelet activation, T cell proliferation, and migration. We show that in our patient, G12E was a somatic variant whose allele frequency decreased over time in the peripheral immune compartment, but remained stable in bone marrow cells, suggesting a differential effect in distinct cell populations. Allogeneic hematopoietic stem cell transplantation fully restored the patient's hemato-immunological phenotype. Our findings define monoallelic RAP1B gain-of-function variants as a cause for constitutive immunodeficiency and thrombocytopenia. The phenotypic spectrum ranged from isolated hematological manifestations in our patient with somatic mosaicism to complex syndromic features in patients with reported germline RAP1B variants.

Oncogenic mutations in the RAS gene are associated with uncontrolled cell growth, a hallmark feature contributing to tumorigenesis. While diverse therapeutic strategies have been diligently applied to treat RAS-mutant cancers, successful targeting of the RAS gene remains a persistent challenge in the field of cancer therapy. In our study, we discover a promising avenue for addressing this challenge.

In this study, we tested the viability of several cell lines carrying oncogenic NRAS, KRAS, and HRAS mutations upon treatment with IkappaBalpha (IκBα) inhibitor BAY 11-7082. We performed both cell culture-based viability assay and in vivo subcutaneous xenograft-based assay to confirm the growth inhibitory effect of BAY 11-7082. We also performed large RNA sequencing analysis to identify differentially regulated genes and pathways in the context of oncogenic NRAS, KRAS, and HRAS mutations upon treatment with BAY 11-7082.

We demonstrate that oncogenic NRAS, KRAS, and HRAS activate the expression of IκBα kinase. BAY 11-7082, an inhibitor of IκBα kinase, attenuates the growth of NRAS, KRAS, and HRAS mutant cancer cells in cell culture and in mouse model. Mechanistically, BAY 11-7082 inhibitor treatment leads to suppression of the PI3K-AKT signaling pathway and activation of apoptosis in all RAS mutant cell lines. Additionally, we find that BAY 11-7082 treatment results in the downregulation of different biological pathways depending upon the type of RAS protein that may also contribute to tumor growth inhibition.

Our study identifies BAY 11-7082 to be an efficacious inhibitor for treating RAS oncogene (HRAS, KRAS, and NRAS) mutant cancer cells. This finding provides new therapeutic opportunity for effective treatment of RAS-mutant cancers.

In this work, we experimentally investigate the potency of high pressure to drive a protein toward an excited state where an inhibitor targeted for this state can bind. Ras proteins are small GTPases cycling between active GTP-bound and inactive GDP-bound states. Various states of GTP-bound Ras in active conformation coexist in solution, amongst them, state 2 which binds to effectors, and state 1, weakly populated at ambient conditions, which has a low affinity for effectors. Zn2+-cyclen is an allosteric inhibitor of Ras protein, designed to bind specifically to the state 1. In H-Ras(wt).Mg2+.GppNHp crystals soaked with Zn2+-cyclen, no binding could be observed, as expected in the state 2 conformation which is the dominant state at ambient pressure. Interestingly, Zn2+-cyclen binding is observed at 500 MPa pressure, close to the nucleotide, in Ras protein that is driven by pressure to a state 1 conformer. The unknown binding mode of Zn2+-cyclen to H-Ras can thus be fully characterized in atomic details. As a more general conjunction from our study, high pressure x-ray crystallography turns out to be a powerful method to induce transitions allowing drug binding in proteins that are in low-populated conformations at ambient conditions, enabling the design of specific inhibitors.

Brain arteriovenous malformations (bAVMs) are direct connections between arteries and veins that remodel into a complex nidus susceptible to rupture and hemorrhage. Most sporadic bAVMs feature somatic activating mutations within KRAS, and endothelial-specific expression of the constitutively active variant KRASG12D models sporadic bAVM in mice. By leveraging 3D-based micro-CT imaging, we demonstrate that KRASG12D-driven bAVMs arise in stereotypical anatomical locations within the murine brain, which coincide with high endogenous Kras expression. We extend these analyses to show that a distinct variant, KRASG12C, also generates bAVMs in predictable locations. Analysis of 15,000 human patients revealed that, similar to murine models, bAVMs preferentially occur in distinct regions of the adult brain. Furthermore, bAVM location correlates with hemorrhagic frequency. Quantification of 3D imaging revealed that G12D and G12C alter vessel density, tortuosity, and diameter within the mouse brain. Notably, aged G12D mice feature increased lethality, as well as impaired cognition and motor function. Critically, we show that pharmacological blockade of the downstream kinase, MEK, after lesion formation ameliorates KRASG12D-driven changes in the murine cerebrovasculature and may also impede bAVM progression in human pediatric patients. Collectively, these data show that distinct KRAS variants drive bAVMs in similar patterns and suggest MEK inhibition represents a non-surgical alternative therapy for sporadic bAVM.

Background: The application of personalized cancer treatment based on genetic information and surgical samples has begun in the field of cancer medicine. However, a biopsy may be painful for patients with advanced diseases that do not qualify for surgical resection. Patient-derived xenografts (PDXs) are cancer models in which patient samples are transplanted into immunodeficient mice. PDXs are expected to be useful for personalized medicine. The aim of this study was to establish a PDX from body fluid (PDX-BF), such as peritoneal and pleural effusion samples, to provide personalized medicine without surgery. Methods: PDXs-BF were created from patients with ovarian cancer who had positive cytology findings based on peritoneal and pleural effusion samples. PDXs were also prepared from each primary tumor. The pathological findings based on immunohistochemistry were compared between the primary tumor, PDX, and PDX-BF. Further, genomic profiles and gene expression were evaluated using DNA and RNA sequencing to compare primary tumors, PDXs, and PDX-BF. Results: Among the 15 patients, PDX-BF was established for 8 patients (5 high-grade serous carcinoma, 1 carcinosarcoma, 1 low-grade serous carcinoma, and 1 clear cell carcinoma); the success rate was 53%. Histologically, PDXs-BF have features similar to those of primary tumors and PDXs. In particular, PDXs-BF had similar gene mutations and expression patterns to primary tumors and PDXs. Conclusions: PDX-BF reproduced primary tumors in terms of pathological features and genomic profiles, including gene mutation and expression. Thus, PDX-BF may be a potential alternative to surgical resection for patients with advanced disease.