Saudi Cultural Missions Theses & Dissertations
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Item Restricted Cancer target discovery for biomarker development, imaging and radionuclide loaded nanoparticle therapy(Saudi Digital Library, 2023-12-04) Shabbir, Rekaya; Choudhury, Ananya; West, Catharine; Smith, TimBackground and aims: Patients with hypoxic muscle invasive bladder cancer (MIBC) have a poor prognosis and overall survival (OS) rate. There is a need to develop biomarkers for informing on hypoxia-targeting therapy. Gene expression signatures can predict benefit from hypoxia modification to improve outcome. Imaging genomics links medical images with molecular profiling to discover imaging biomarkers that could reflect hypoxia. Molecular radiotherapy (MRT) targets specific receptors expressed by cells. The overexpression of EGFR also associates with poor survival rates, EGFR inhibitors are promising but tumour heterogeneity is problematic. The thesis aims were to: 1) identify genes upregulated by hypoxia in bladder cancer cells; 2) investigate whether the West 24-gene bladder hypoxia signature is sensitive to changes in oxygen levels; 3) use MRI to identify hypoxia in large and small tumours in vivo; 4) identify new hypoxia-associated gene panels from transcriptomic data generated in vitro and in vivo; 5) identify bladder cancer hypoxic biomarkers and surface membrane targets for MRT using proteomics in MIBC; and 6) study the uptake and dose-distributions of EGFR-targeted 177Lu or 90Y radiolabelled-AuNPs. Methods: 1) Six BC cell lines (HT1376, T24, J82, UMUC3, RT4, RT112) were exposed to normoxia (21% O2) and hypoxia (1%, 0.1% and 0.2% O2) for 24h. RNA was extracted, transcriptomic data generated using Clariom S Microarrays and expression of hypoxia upregulated genes identified. 2) The data were used to explore changes in West 24-gene signature scores. 3) Small (300mm3) and large (700mm3) xenografts were established for HT1376 MIBC cells. Hypoxia was identified using pimonidazole (PIMO), OE-MRI and DCE-MRI. Differential gene expression was determined. 4) Gene panels were derived from in vitro and in vivo transcriptomic data and tested (log-rank Mantel Cox test) in a TCGA bladder cancer cohort (n=412). Hypoxia scores were generated using the median expression of the genes in a signature/panel. 5) HT1376, T24 and J82 cells were cultured in normoxia (21% O2) and hypoxia (1% and 0.1% O2) for 24h and 48h. Proteins were extracted and analysed using LC-MS and SWATH-MS, and the data used to identify surface membrane targets. Differential expression of EGFR and hypoxia markers (CAIX, GLUT-1) was measured using transcriptomics, proteomics, western blot and EGFR-ELISA. 6) Anti-EGFR conjugated radiolabelled (177Lu or 90Y) AuNPs were used to study dose distributions in vivo. Results: 1) 77 genes were significantly upregulated (padj≤ 0.001) in hypoxia (0.1% O2) across ≥3 cell lines. Three genes (DPYSL2, SYDE1, SLC2A3) were in both the West 24-gene signature and new 77-gene panel. 2) The expression of the 24-gene West signature increased with decreasing O2 levels. 3) Hypoxic regions were identified in small and large xenografted tumours using a combination of OE-MRI and DCE-MRI approaches. The in vivo transcriptomics analysis identified gene expression differences between PIMO-high(hypoxic) and PIMO-low(normoxic) regions and differences in HSs generated from the 24-gene signature (p<0.0052) and the new 77-gene panel (p<0.0025). 4) Gene signatures/panels were prognostic for overall survival: 24-gene (p<0.000064), 77-gene (p<0.01), 3 common genes (p<0.0013). 5) 26 proteins had consistently higher expression in hypoxia across all three cell lines. A gene panel based on the 26 proteins was prognostic in the TCGA cohort (p<0.00065). Eleven plasma membrane proteins were identified as upregulated under hypoxia. No significant differential expression of EGFR was seen in BC cells by hypoxia. The expression of hypoxia markers (CAIX and GLUT-1) was significantly increased by hypoxia using different measurement approaches in all bladder cells. 6) The coefficient of variation of EGFR-targeted 90Y-radiolabelled-AuNPs was less than EGFR-targeted 177Lu-radiolabelled-AuNPs in xenografted tumours. Conclusions: 1) Hypoxia influences the expression of many common genes across different bladder cancer cell lines. 2) The West 24-gene bladder hypoxia score is sensitive to changes in O2 levels in vitro showing it reflects differences in hypoxia. 3) Gene panels derived from hypoxic cells in vitro inform on hypoxia and prognosis 4) The West 24-gene signature performed best as a biomarker of hypoxia. 5) Proteomic profiling identified cell membrane markers to study for MRT. 6) Anti-EGFR radionuclides labelled AuNPs provided insight about the heterogeneity and dosimetry of MRT.5 0Item Restricted SYNTHESIS AND EVALUATION OF NOVOBIOCIN ANALOGUES AS POTENTIAL INHIBITORS OF POLYMERASE THETA POLΘ IN DNA DAMAGE AND REPAIR(University of Arkansas at Little Rock, 2025) Albuhluli, Mohammed; Anindya, Ghosh; Darin, JonesKilling tumors while leaving normal cells unharmed is the goal of precision cancer therapy, a challenging feat that is enabled by targeting tumor-specific vulnerabilities [1]. Targeting Polθ potentiates PARP inhibitors (PARPi) in specifically killing homology-directed repair (HDR)-deficient tumor cells and re-sensitize PARPi resistant tumor cells [1]. The induced essentiality between Polθ and HDR-deficiency underscores the value of Polθ as a therapeutic target in the context of tumors with HDR genetic mutations [1]. The helicase-like domain (HLD) is a super family 2 (SF2)-type domain with DNA-dependent ATPase activity [1]. We previously discovered that the antibiotic NVB acts as an inhibitor of N-terminal HLD of Polθ [1]. Consequently, a Phase I clinical trial of Novobiocin (NVB) is currently underway in patients with tumors that harbor aberrant DNA repair genes [1]. To inform enigmatic theta-mediated end joining (TMEJ) and support ongoing preclinical and clinical studies, we therefore investigated the mechanism of action of NVB-mediated inhibition of Polθ ATPase activity [1]. By combining hydrogen deuterium exchange-mass spectrometry (HX-MS), biochemical assays, microscale thermophoresis (MST), cellular assays and computational modelling, we determined that NVB is a non-ATP competitive inhibitor that binds to an allosteric site near the ssDNA binding channel in the ATPase core [1]. This is contrary to the current view of NVB as an ATP competitive inhibitor of DNA gyrase [1]. This NVB binding mode blocks ssDNA binding and inhibits ssDNA-mediated stimulation of Polθ ATPase activity [1]. Importantly, we find that NVB blocks Polθ binding to ssDNA both in vitro and in cells [1]. Using novobiocic acid (the aglycone of NVB), we investigated the orientation of NVB binding and established the contribution of the sugar group in enhancing the potency of NVB [1]. Our study identified the NVB binding pocket and provides a path for optimization and investigation of the importance of ssDNA binding for Polθ biological functions at double-strand breaks (DSBs) and stalled replication forks [1].20 0Item Restricted Integrative Genomic Analysis of Cytogenetically Normal Acute Myeloid Leukaemia(University College London, 2025) Alhawaj, Ali Fouad; Mansour, MarcAcute Myeloid Leukaemia (AML) is a haematological malignancy characterized by increased proliferation and blocked differentiation of haematopoietic progenitors. Cytogenetically normal AML (CN-AML) accounts for approximately 50% of all AML cases, with a 5-year survival rate of approximately 50%. Approximately 40% of patients exhibit primary resistance to induction chemotherapy; however, the molecular basis remains poorly understood. Additionally, high SETBP1 expression has been implicated in AML development, although the underlying mechanism remains unclear. This thesis aimed to explore the genomic and transcriptomic profiles of primary-resistant CN-AML in adults, and SETBP1 allele-specific expression (ASE) as a potential cause of high SETBP1 expression. Through whole-exome and RNA sequencing of resistant and matched remission samples, we identified a high presence of UBTF-TD in CN-AML (12%) and a higher incidence of WT1 mutations in the resistant versus remission cohorts (29% vs. 10%, p=0.005). However, CRISPR knockout of WT1 in a 416B mouse model did not confer resistance to Cytarabine or Daunorubicin RNA sequencing indicated enrichment of senescence signatures in the resistant cohort, along with novel gene fusions of LATS2-ZMYM2 (20.9%) and LATS2-HMGB1 (14.3%) in CN-AML. Lastly, integrative genomic and transcriptomic analyses revealed GATA2 and SETBP1 ASE, including a novel non-coding SETBP1 mutation, potentially driving its high expression. Future studies are required to validate UBTF-TD lesions and refine the WT1 knockout, potentially revealing new resistance mechanisms amenable to treatment. LATS2 fusions also require validation to clarify their impact on the tumour-suppressive Hippo pathway. Finally, long-read and whole-genome sequencing may reveal additional mechanisms underlying GATA2 pathogenic expression, whereas functional assays of the novel non-coding SETBP1 variant may elucidate its role in driving AML. These findings may ultimately refine the prognosis and inform new therapeutic strategies for high-risk CN-AML.13 0Item Restricted Assessment of Immunotherapy-Related Adverse Events Among Patients with Cancer in Saudi Arabia: A Mixed Methods Study(Queensland university of techonology, 2024) Alquzi, Fatimah; Bradford, NatalieThis thesis contributes significantly to cancer care by focusing on patients undergoing immunotherapy in Saudi Arabia. it is the first study to explore the challenges these patients face, offering valuable insight into their experience. the research translated and validated an immunotherapy assessment tool and assessed its real world use by evaluating its acceptability, feasibility, and clinical utility. this study deepens the understanding of immune related adverse events and provide critical perspectives for clinicians, patients, and researcher. Ultimately, it contributes to improving the management of adverse events in cancer immunotherapy. Background: Cancer is a rapidly growing healthcare system challenge, with more than 19.3 million incidences recorded globally in 2020; this is projected to surpass 29.5 million by 2040. The emergence of immunotherapy has positively changed many advanced cancer outcomes and improved survival rates. Despite immunotherapy being an efficacious and reliable treatment option for cancer, its success is tempered by associated immune-related adverse events (irAEs). Limited understanding of proactive irAE assessment further complicates this issue. Patient Reported Outcome (PRO) measures are standardised tools used to systematically collect data from patients about their health status, symptoms, functioning, and well-being, and are increasingly advocated for use in routine clinical care. However, their use in clinical care, and more specifically to assess irAEs and symptoms, is an understudied area. Objectives: To investigate the feasibility, acceptability, and usefulness of systematic assessment of irAEs from the perspectives of patients with cancer living in Saudi Arabia. Methods: The doctorate project involved five inter-related studies, underpinned by the theory of Symptoms Experience in Time (SET), a conceptual framework aimed at understanding the temporal dynamics of symptom manifestation and progression. In Study 1, a systematic literature review was completed. A comprehensive search strategy was employed to identify relevant literature on symptom assessment and management strategies related to irAEs in cancer patients. The review identified a PRO tool developed specifically for irAEs to assess 20 symptom and six interference items. In Study 2, the PRO tool identified for irAEs assessment from the review underwent robust translation from English into Arabic using the Brislin translation method. This involved forward and backward translations, consensus committees with health experts and linguists, and iterative adjustments to ensure linguistic accuracy and cultural appropriateness. Study 3 was an observational study undertaken in Saudi Arabia to evaluate the psychometric properties of the tool among Saudi Arabian cancer patients undergoing immunotherapy. The assessment involved mixed methods, including cognitive interviewing to assess item clarity and relevance, content validity and test–retest reliability analysis, and a post-assessment feedback survey to assess acceptability. Study 4 was a prospective observational cohort study over four weeks that investigated the feasibility, acceptability, and usefulness of the translated tool to assess irAEs and symptom experiences of patients undergoing immunotherapy for cancer in Saudi Arabia. Finally, in Study 5, a subset of participants from Study 4 participated in in-depth semi-structured interviews, which were analysed using qualitative content analysis. Results: Study 1: The systematic literature review identified a suitable PRO tool for assessing diverse irAEs among cancer patients undergoing immunotherapy. The review also identified gaps in evidence, including the unclear frequency of symptom assessment and the role of non-pharmacological approaches for managing mild irAEs. In Study 2, the PRO tool was translated, creating the Arabic version of the tool: the Arabic Immunotherapy Symptom Assessment Inventory (AISAI). Study 3 evaluated the psychometric properties of the AISAI, which demonstrated content validity, reliability, linguistic precision, and cultural relevance. The Cronbach’s alpha coefficients for the internal consistency were calculated as 0.90 for the 20 symptom items and 0.88 for the interference scale, indicating satisfactory reliability. The test–retest reliability, assessed through intraclass correlation coefficients (ICC), showed excellent agreement between Time 1 and Time 2, with ICC values above 0.90. In Study 4, a real-world, 4-week evaluation involving a cohort of 69 patients undergoing cancer immunotherapy treatment was completed. The feasibility and acceptability of administering the AISAI were high, with 97.1% affirming its acceptability and applicability. The five most prevalent and severe symptoms, based on mean scores, were: numbness or tingling; pain; rash or skin change; interference with general activity; and impaired walking. Over the 4- week immunotherapy period, there was a notable increase in the severity of symptoms, with statistically significant changes observed. The number of participants with moderate (score 4–6) and severe (score 6–10) symptoms increased, indicating a worsening pattern over time. In Study 5, a qualitative evaluation affirmed that the AISAI was perceived as a valuable tool for early recognition and assessment of irAEs, with a preference for routine usage. The evaluation also highlighted knowledge gaps, emphasising the need for educational interventions to enhance comprehension and management capabilities among patients. Conclusion: This thesis represents a novel contribution to the field, particularly in the context of cancer patients undergoing immunotherapy treatment in Saudi Arabia. It introduces an innovative approach by incorporating PROs in Saudi Arabia. This marks a significant advancement in the assessment practices related to irAEs. Notably, it is the first study to explore the experience of irAEs in Saudi Arabia using PRO, providing a comprehensive understanding of the challenges faced by these patients. Moreover, this research pioneers the investigation of the use of the AISAI in real-world settings for cancer patients undergoing immunotherapy. It assesses the tool’s acceptability, feasibility, and usefulness, shedding light on its practical implications in the clinical setting. The research contributes a valid and comprehensive tool, the AISAI, designed specifically for assessing irAEs in Arabic cancer patients. This research makes a valuable contribution to clinicians, patients, and researchers, enhancing the overall understanding and approach to assessment of adverse events in the context of cancer immunotherapy.22 0Item Restricted Subcellular Location-Dependent Regulation of Interferon-Induced Transmembrane Protein 1 in Glioblastoma(The University of Edinburgh, 2024) Mubarak, Rawan; Ball, KathrynGlioblastoma multiforme (GBM) is one of the most aggressive and lethal brain cancers, known for its highly invasive nature and resistance to conventional therapies. Central to this resistance is the presence of glioblastoma stem cells (GSCs), which contribute to tumour recurrence and heterogeneity. This thesis investigates the roles of interferon-induced transmembrane proteins (IFITMs), specifically IFITM1 and IFITM3, within GSCs and their potential as therapeutic targets. The study provides a detailed analysis of IFITM1’s expression, subcellular localisation, and interaction with other proteins in response to interferon stimulation, employing advanced molecular techniques such as co-immunoprecipitation, immunofluorescence microscopy, and proteomic analysis. Key findings include the discovery that IFITM3 plays a critical role in regulating IFITM1’s expression and localisation, with significant implications for IFITM1’s function in cancer cell biology. This thesis also contributes to validating a novel interaction between IFITM1 and Lysosomal-associated membrane protein 1, suggesting a potential role for IFITM1 in autophagy, which could be pivotal in GBM’s resistance to treatment. These insights not only advance the understanding of IFITM proteins in GSCs but also highlight their potential as targets for therapeutic intervention in GBM. This work lays the foundation for future studies aimed at manipulating IFITM proteins to develop novel strategies for overcoming GBM treatment resistance.46 0Item Restricted Role of somatic copy number alterations in the aetiology and prognosis of Acute Myeloid Leukaemia(Newcastle University, 2024-02) Alharbi, Abrar Abdulghani; James, AllanAcute Myeloid Leukaemia (AML) is a group of highly heterogeneous haematological malignancies that arises from the accumulation of acquired genetic lesions, including point mutations, translocations, and DNA copy number alterations (CNAs) that confer a survival advantage to the leukaemic cell. The identification and characterisation of these aberrations have not only shed light on the pathogenesis of AML but also have improved patient stratification and the selection of therapeutic strategies. Despite these advances, drug resistance and relapse remain persistent clinical challenges, which may reflect the presence of as yet undetected alterations that influence disease progression and outcome. Recent advances in high throughput platforms such as microarray‐based genotyping technologies have revealed previously unrecognised cryptic chromosomal aberrations associated with DNA copy number changes. Given the heterogeneity of AML genomes, input from these platforms can potentially supplement cytogenetic data to improve prognostication and guide treatment decisions, and perhaps lend further insight into the mechanisms underlying AML pathogenesis. In this study, we analysed SNP‐microarray data from a large cohort of over 3000 AML cases for CNAs and copy‐neutral regions of homozygosity. In addition to providing a comprehensive overview of the landscape of acquired CNAs and regions of homozygosity in AML, this large cohort enabled us to identify and validate recurrent novel focal CNAs. Among validated gene targets affected by focal CNA is MIR4447, a previously uncharacterised microRNA. To investigate the potential role of MIR4447 in AML pathogenesis, we developed both gain‐ and loss‐of‐function cell models via gene overexpression and CRISPR/cas9‐mediated gene editing, respectively. These models were interrogated using RNA sequencing to analyse the transcriptional impact of miR‐4447 modulation. Our findings suggest that miR‐4447 has a multifaceted and context‐dependant role in regulating cellular functions, impacting energy metabolism, ribosome synthesis, immune response, and possibly leukaemogenesis through alterations in nutrient transport, mitochondrial function, and cell migration. Collectively, our findings contribute to our understanding of the genomic intricacies of AML and highlight the need for further research to investigate the downstream targets of miR‐4447, its effects in different cellular contexts, and its interaction with other regulatory molecules.7 0Item Restricted Field Cancerization and Microbiome Effects on Lung Cancer: A Source of Early Detection Biomarkers to Improve Patients’ Outcome(George Mason University, 2024-08-16) Alhammad, Rayan; Luchini, AlessandraLung cancer results in more deaths than any other cancer in the United States and worldwide, with non-small cell lung cancer (NSCLC) accounting for most cases. Diagnosis typically involves chest imaging, molecular testing, and biopsy. However, most patients are diagnosed at advanced stages, with only a 6% chance of a 5-year survival rate. In contrast, early-stage diagnosis and treatment can result in a favorable prognosis, with a high 5-year survival rate of 70-90%. The concept of tumor field cancerization describes a phenomenon where exposure to carcinogens can cause histologic changes in large areas of tissue, creating a field of pre-malignant cells that can eventually develop into tumors. Additionally, microbiota dysbiosis might influence tumor development. Studies have identified several commensal bacteria present in the lower airway tracts, such as Streptococcus, Prevotella, and Veillonella. The high mortality rate of lung cancer is often attributed to i) its late-stage diagnosis, ii) aggressive nature given its ability to metastasize early in the disease process complicating treatment and reducing survival rates, and iii) significant therapeutic challenges despite current treatments such as surgery, chemotherapy, radiation therapy, targeted therapy and immunotherapy. Despite advancements, the survival rate for advanced lung cancer remains low. To address this challenge, our research focuses on identifying risk protein biomarkers that are associated with the earliest molecular changes indicative of an ongoing tumorigenic process, thus offering significant potential for early intervention. Our study investigates the phenotypic molecular changes in the bronchial tree of NSCLC patients in light of the field cancerization theory and correlates these findings with blood biomarkers to support the future development of a non-invasive risk assessment test. Using enhanced liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomic analysis and two independent cohorts of lung cancer patients (N=18, and N=263) with matched plasma and bronchial tree tissue specimens, we identified a set of 6 and 13 candidate risk plasma biomarkers with tissue origin. Additionally, we explored the microbiome proteome composition in NSCLC patient tissue and plasma to support future characterization of its potential role in cancer development. Risk biomarkers will enable the evaluation of individuals at high risk, guiding necessary lifestyle adjustments and facilitating the development of personalized prevention plans and therapies.52 0Item Restricted The potential of natural products to be anticancer agents(University of Aberdeen, 2018-11-24) Aljohani, Moaath Mohammad A; Wallace, Heather MBackground and Purpose Natural products have been a valuable source not only for foods but also for medicines. Cancer is one of the chronic, non-curable and fatal disease. Studies have shown that natural products have a great potential in treating several medical conditions including cancer. Experimental Approach The main methods used to carry out this study were cell culture, Trypan blue exclusion assay, MTT cytotoxicity assay and Lowry assay. These methods used to investigate the effect of curcumin and resveratrol on A549 cell line growth and survival. Key Results Both curcumin and resveratrol indicated interesting results, leading to a decline in total number of viable cells in addition to protein content of A549 cell line. Conclusion and Implications Curcumin, resveratrol and other natural products should be examined thoroughly owing to their availability and promising future that they have shown, which may end with the discovery of novel agents that can tackle the global problem of cancer.51 0Item Restricted Advancing Oncolytic Virotherapy: The Role of Chemical Sensitizers in Enhancing Viral Oncolysis in Resistant Cancers(University of Ottawa, 2024-07-28) Alwithenani, Akram; Diallo, Jean-SimonOncolytic virotherapy, leveraging viruses to target cancer selectively, has shown promise with the FDA-approved oncolytic herpes simplex virus-1 (HSV-1) for melanoma treatment. However, the efficacy of oncolytic viruses (OVs) varies across cancer types, highlighting the need for strategies to sensitize resistant tumors. This thesis investigates the potential of Dimethyl fumarate (DMF), its analog Tepilamide Fumarate (TPF), and novel synthetic small molecules identified from a high-throughput screen to enhance OV effectiveness in cancer therapy. DMF, approved for multiple sclerosis and psoriasis, and TPF, under trial for psoriasis, were evaluated for their ability to boost HSV-1 and vesicular stomatitis virus (VSVΔ51) activity against cancer cells. Our findings reveal that pre-treatment with DMF or TPF significantly increases HSV-1 and VSVΔ51 replication in various cancer cell lines, including melanoma, and improves viral oncolysis. Notably, both DMF and TPF enhance OV infection in mouse-derived tumor cores and human tumor samples, while TPF exhibits a remarkable capacity to heighten VSVΔ51 infection and cell killing, outperforming DMF in vitro. Both compounds achieve these effects by downregulating the interferon (IFN) pathway, rendering cancer cells more susceptible to viral infection. Additionally, we demonstrate the ability of DMF and TPF to boost gene therapy vectors' transduction efficiency, which points to the broader utility of these drugs in gene therapy. Further exploration through a high-throughput screen identified several small molecules that sensitize human renal carcinoma cells to HSV-1 and VSVΔ51, highlighting potential new avenues for overcoming tumor resistance to OVs. These compounds enhance viral replication and oncolysis, presenting a promising path for future oncolytic virotherapy research and development. The synergistic potential of combining approved therapies like DMF with OVs, the promising effects of TPF, and newly identified small molecule sensitizers underscore the feasibility of enhancing OV efficacy in resistant cancers. This study not only broadens our understanding of how small molecules can potentiate oncolytic virotherapy but also sets the stage for clinical evaluation and the development of more effective, personalized cancer treatment strategies. Collectively, these findings advocate for further investigation into DMF, TPF, and other sensitizing compounds to unlock their full therapeutic potential in oncolytic virotherapy.14 0Item Restricted Rme-6, a Novel Regulator for EGFR Trafficking and Signaling(University of Sheffield, 2024-02-21) Alshahrani, Fahad Ayidh M; Smythe, ElizabethThe Epidermal Growth Factor Receptor (EGFR) is a key regulator for critical cellular processes including proliferation, migration, and apoptosis. Dysregulation of EGFR trafficking and signaling plays a crucial role in cancer development and contributes significantly to resistance to chemotherapy. This thesis examines the novel regulatory role of Rme-6, a Rab5 guanine nucleotide exchange factor (GEF), in modulating EGFR signaling by influencing its endocytic flux, a key determinant in the spatial and temporal dynamics of EGFR-mediated signaling pathways. Through a series of molecular and cellular experiments, I demonstrate that Rme-6 critically influences EGFR endocytic trafficking. Specifically, loss of Rme-6 results in increased accumulation of EGFR in APPL1-positive endosomes. This accumulation alters the downstream signaling fate of ERK1/2 by modulating its nuclear translocation. I have shown that Rme-6 has a positive effect on ERK1/2 signaling, while its disruption leads to aberrant ERK1/2 activity. This change in ERK1/2 signaling correlates with altered cell proliferation rates, suggesting a potential mechanism for cancer progression. Additionally, I reveal that Rme-6 may act as a scaffold for CK2 to phosphorylate ERK1/2 on its SPS motif, which is essential for its nuclear translocation and activation of transcription factors such as c-Fos. This phosphorylation impacts gene expression and subsequent cell fate decisions. This research not only advances our understanding of the molecular dynamics of EGFR signaling but also proposes Rme-6 as a potential therapeutic target in cancers characterized by dysregulated EGFR signaling pathways.16 0
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