Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias

Hu, Chun; Leche, C.A.; Kiyatkin, Anatoly; Yu, Zhaolong; Stayrook, Steven E.; Ferguson, Kathryn M.; Lemmon, Mark A.

doi:10.1038/s41586-021-04393-3

Cited by 55 publications

(47 citation statements)

References 63 publications

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“…Some of those genes, such as CDKN2A (Kraus et al, 2001;Hu et al, 2017), CA9 (Said et al, 2007), and HSPB1 (Rajesh et al, 2020), were also found in previous reports, which further confirmed the feasibility of our study design. Further analysis found that CDKN2A, TP53, IDH1, and EGFR were still the most abnormally altered genes in glioblastoma (Figure 1) (Kraus et al, 2001;Hu et al, 2017;Hu et al, 2022;Hu et al, 2018), while the most common variation in SNP was C > T (Figure 1C) (McDonald et al, 2013;Mistry et al, 2018). This was similar to the mutation frequency of TP53 and IDH1 obtained in the immunohistochemistry of clinical samples (Table 2; Figure 6).…”

Section: Discussionsupporting

confidence: 71%

Comprehensive Analyses of Ferroptosis-Related Alterations and Their Prognostic Significance in Glioblastoma

Tian¹,

Liu

Zhang

et al. 2022

Front. Mol. Biosci.

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Background: This study was designed to explore the implications of ferroptosis-related alterations in glioblastoma patients.Method: After obtaining the data sets CGGA325, CGGA623, TCGA-GBM, and GSE83300 online, extensive analysis and mutual verification were performed using R language-based analytic technology, followed by further immunohistochemistry staining verification utilizing clinical pathological tissues.Results: The analysis revealed a substantial difference in the expression of ferroptosis-related genes between malignant and paracancerous samples, which was compatible with immunohistochemistry staining results from clinicopathological samples. Three distinct clustering studies were run sequentially on these data. All of the findings were consistent and had a high prediction value for glioblastoma. Then, the risk score predicting model containing 23 genes (CP, EMP1, AKR1C1, FMOD, MYBPH, IFI30, SRPX2, PDLIM1, MMP19, SPOCD1, FCGBP, NAMPT, SLC11A1, S100A10, TNC, CSMD3, ATP1A2, CUX2, GALNT9, TNFAIP6, C15orf48, WSCD2, and CBLN1) on the basis of “Ferroptosis.gene.cluster” was constructed. In the subsequent correlation analysis of clinical characteristics, tumor mutation burden, HRD, neoantigen burden and chromosomal instability, mRNAsi, TIDE, and GDSC, all the results indicated that the risk score model might have a better predictive efficiency.Conclusion: In glioblastoma, there were a large number of abnormal ferroptosis-related alterations, which were significant for the prognosis of patients. The risk score-predicting model integrating 23 genes would have a higher predictive value.

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Section: Discussionsupporting

confidence: 71%

Comprehensive Analyses of Ferroptosis-Related Alterations and Their Prognostic Significance in Glioblastoma

Tian¹,

Liu

Zhang

et al. 2022

Front. Mol. Biosci.

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“…First, high- and low-affinity ligands are expected to bind to their receptor with different affinities, which we modeled by varying the dissociation rate of ligand-receptor complexes using a scaling parameter β. Second, low-affinity ligands have been reported to produce structurally different EGFR dimers compared to high-affinity ligands, thereby reducing the dimerization affinity of ligand-bound receptors (Freed et al, 2017; Hu et al, 2022); we modeled this dimerization affinity by varying the dissociation rate of ligand-bound dimers using a scaling parameter γ.…”

Section: Resultsmentioning

confidence: 99%

“…To validate the prediction of our model, we experimentally altered the dimerization affinity of EGFR and monitored signaling responses using pYtags. We turned to glioblastoma multiform (GBM)-associated mutations in the extracellular domain of EGFR (R84K and A265V point mutations), which were previously shown to increase the dimerization affinity of EREG- and EPGN-bound receptors (Hu et al, 2022). We first modeled these GBM-associated mutations in EGFR by decreasing β and γ by 6-fold and 650-fold, respectively (Hu et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

“…We turned to glioblastoma multiform (GBM)-associated mutations in the extracellular domain of EGFR (R84K and A265V point mutations), which were previously shown to increase the dimerization affinity of EREG- and EPGN-bound receptors (Hu et al, 2022). We first modeled these GBM-associated mutations in EGFR by decreasing β and γ by 6-fold and 650-fold, respectively (Hu et al, 2022). These modifications led to the prediction that 20 ng/mL EREG would induce a stronger, more gradual signaling response in GBM-associated mutants compared to the wild-type receptor ( Figure 3D ).…”

Section: Resultsmentioning

confidence: 99%

“…Some classes of receptors can form homo-or heterodimers, further diversifying signaling responses (Del Piccolo et al, 2017;Harari and Yarden, 2000;Kanakaraj et al, 1991). Moreover, a single RTK can bind to many different ligands that are capable of inducing distinct conformational changes to tune downstream signaling dynamics (Freed et al, 2017;Hu et al, 2022). These observations underscore the substantial complexity present at even the uppermost node of the RTK signaling network: the interaction between receptors and their ligands.…”

Section: Introductionmentioning

confidence: 99%

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pYtags enable spatiotemporal measurements of receptor tyrosine kinase signaling in living cells

Farahani

Yang

Mesev

et al. 2022

Preprint

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Receptor tyrosine kinases (RTKs) are major signaling hubs in metazoans, playing crucial roles in cell proliferation, migration, and differentiation. However, few tools are available to measure the activity of a specific RTK in individual living cells. Here, we present pYtags, a modular approach for monitoring the activity of a user-defined RTK by live-cell microscopy. pYtags consist of an RTK modified with a tyrosine activation motif that, when phosphorylated, recruits a fluorescently labeled tandem SH2 domain with high specificity. We show that pYtags enable the monitoring of a specific RTK on seconds-to-minutes time scales and across subcellular and multicellular length scales. Using a pYtag biosensor for epidermal growth factor receptor (EGFR), we quantitively characterize how signaling dynamics vary with the identity and dose of activating ligand. We show that orthogonal pYtags can be used to monitor the dynamics of EGFR and ErbB2 activity in the same cell, revealing distinct phases of activation for each RTK. The specificity and modularity of pYtags opens the door to robust biosensors of multiple tyrosine kinases and may enable engineering of synthetic receptors with orthogonal response programs.

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Current status of precision oncology in adult glioblastoma

Weller,

Potthoff,

Zeyen

et al. 2024

Molecular Oncology

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The concept of precision oncology, the application of targeted drugs based on comprehensive molecular profiling, has revolutionized treatment strategies in oncology. This review summarizes the current status of precision oncology in glioblastoma (GBM), the most common and aggressive primary brain tumor in adults with a median survival below 2 years. Targeted treatments without prior target verification have consistently failed. Patients with BRAF V600E‐mutated GBM benefit from BRAF/MEK‐inhibition, whereas targeting EGFR alterations was unsuccessful due to poor tumor penetration, tumor cell heterogeneity, and pathway redundancies. Systematic screening for actionable molecular alterations resulted in low rates (< 10%) of targeted treatments. Efficacy was observed in one‐third and currently appears to be limited to BRAF‐, VEGFR‐, and mTOR‐directed treatments. Advancing precision oncology for GBM requires consideration of pathways instead of single alterations, new trial concepts enabling rapid and adaptive drug evaluation, a focus on drugs with sufficient bioavailability in the CNS, and the extension of target discovery and validation to the tumor microenvironment, tumor cell networks, and their interaction with immune cells and neurons.

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Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias

Cited by 55 publications

References 63 publications

Comprehensive Analyses of Ferroptosis-Related Alterations and Their Prognostic Significance in Glioblastoma

Comprehensive Analyses of Ferroptosis-Related Alterations and Their Prognostic Significance in Glioblastoma

pYtags enable spatiotemporal measurements of receptor tyrosine kinase signaling in living cells

Current status of precision oncology in adult glioblastoma

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