Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development

Binder, Zev A.; Thorne, Amy Haseley; Bakas, Spyridon; Wileyto, E. Paul; Bilello, Michel; Akbari, Hamed; Rathore, Saima; Ha, Sung Min; Zhang, Logan; Ferguson, Cole; Dahiya, Sonika; Bi, Wenya Linda; Reardon, David A.; Idbaïh, Ahmed; Felsberg, Joerg; Hentschel, Bettina; Weller, Michael; Bagley, Stephen; Morrissette, Jennifer J.D.; Nasrallah, MacLean P.; Ma, Jianhui; Zanca, Ciro; Scott, Andrew M.; Orellana, Laura; Davatzikos, Christos; Furnari, Frank B.; O’Rourke, Donald M.

doi:10.1016/j.ccell.2018.06.006

Cited by 144 publications

(123 citation statements)

References 61 publications

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“…As a consequence, we show that heterogeneous ECD mutations, and not only EGFRvIII, are responsive to mAb806, which, importantly, has a synergistic tumor-inhibitory effect when combined with TKI-2s binding to the same conformational state. Our findings unexpectedly bring together two independent lines of research on GBM mutations (5) and mAb806 (10), hinting at a much broader spectrum for this antibody, far beyond our previous study (17) and, importantly, paving the way for the rational extraintracellular cotargeting of EGFR-mutated tumors.…”

supporting

confidence: 50%

“…Growing evidences indicate that the sole presence of EGFR-KD mutations in a tumor predicts positive responses to anti-EGFR therapy (45). If the same holds true for ECD mutations, 806-convergence will open a wider application spectrum of mAb806 than ever suggested (17), and together with TKI-driven ECD conversion (Figs. 5C and 6F), will pave a rational basis for extraintracellular EGFR targeting.…”

Section: Discussionmentioning

confidence: 95%

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Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope

Orellana

Thorne

Lema

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Epidermal growth factor receptor (EGFR) signaling is initiated by a large ligand-favored conformational change of the extracellular domain (ECD) from a closed, self-inhibited tethered monomer, to an open untethered state, which exposes a loop required for strong dimerization and activation. In glioblastomas (GBMs), structurally heterogeneous missense and deletion mutations concentrate at the ECD for unclear reasons. We explore the conformational impact of GBM missense mutations, combining elastic network models (ENMs) with multiple molecular dynamics (MD) trajectories. Our simulations reveal that the main missense class, located at the I-II interface away from the self-inhibitory tether, can unexpectedly favor spontaneous untethering to a compact intermediate state, here validated by smallangle X-ray scattering (SAXS). Significantly, such intermediate is characterized by the rotation of a large ECD fragment (N-TR1), deleted in the most common GBM mutation, EGFRvIII, and that makes accessible a cryptic epitope characteristic of cancer cells. This observation suggested potential structural equivalence of missense and deletion ECD changes in GBMs. Corroborating this hypothesis, our FACS, in vitro, and in vivo data demonstrate that entirely different ECD variants all converge to remove N-TR1 steric hindrance from the 806epitope, which we show is allosterically coupled to an intermediate kinase and hallmarks increased oncogenicity. Finally, the detected extraintracellular coupling allows for synergistic cotargeting of the intermediate with mAb806 and inhibitors, which is proved herein. cancer | mutational heterogeneity | structural convergence | intermediate | cryptoepitope

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supporting

confidence: 50%

Section: Discussionmentioning

confidence: 95%

Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope

Orellana

Thorne

Lema

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Great advances have been made in molecular targeted therapies in multiple cancers, such as lung cancer and melanoma . Although sorafenib, lenvatinib and regorafenib have been approved by FDA for the therapy of HCC, the global survival benefits for these drugs are only about 3‐6 months .…”

Section: Discussionmentioning

confidence: 99%

Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

Wang

Guo

Nampoukime

et al. 2020

J Cellular Molecular Medi

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Hepatocellular carcinoma (HCC) is a main cause of cancer‐related deaths globally. Long non‐coding RNAs (lncRNAs) play important roles in diverse cancers. Our previous microarray‐based lncRNA profiling showed that LINC00467 was highly expressed in HCC. Here, we further explored the expression, role and functional mechanism of lncRNA LINC00467 in HCC. Our findings revealed that LINC00467 was up‐regulated in HCC tissues and HCC cell lines. Increased expression of LINC00467 was positively associated with tumour size and vascular invasion. In vitro functional experiments revealed that LINC00467 accelerated HCC cell proliferation, cell cycle progression and migration and reduced HCC cell apoptosis. In vivo functional assays revealed that LINC00467 drove HCC xenograft growth and HCC cell proliferation and repressed HCC cell apoptosis in vivo. Moreover, LINC00467 inhibited NR4A3 post‐transcriptionally via interacting with NR4A3 mRNA to form double‐stranded RNA, which was further degraded by Dicer. The expression of NR4A3 was inversely associated with LINC00467 in HCC tissues. Functional rescue assays found that restore of NR4A3 expression blocked the oncogenic roles of LINC00467 in HCC. Taken together, our results demonstrated that lncRNA LINC00467 was a novel highly expressed and oncogenic lncRNA in HCC via inhibiting NR4A3. Targeting LINC00467 or enhancing NR4A3 may be potential therapeutic strategies against HCC.

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“…For example, methylation status of the gene encoding O6‐methylguanine‐DNA methyltransferase (MGMT) predicts the response to TMZ (Nam & de Groot, ). Moreover, heritable genetic aberrations of the epidermal growth factor receptor (EGFR) have been implicated in GBM progression and survival (Binder et al, ). Overexpression of EGFR was identified in 50–60% of patients with GBM and its expression is strictly correlated to a poor prognosis of the disease (Xin et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…For example, methylation status of the gene encoding O6-methylguanine-DNA methyltransferase (MGMT) predicts the response to TMZ (Nam & de Groot, 2017). Moreover, heritable genetic aberrations of the epidermal growth factor receptor (EGFR) have been implicated in GBM progression and survival (Binder et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Boswellic acid has anti‐inflammatory effects and enhances the anticancer activities of Temozolomide and Afatinib, an irreversible ErbB family blocker, in human glioblastoma cells

Barbarisi

Sena

et al. 2019

Phytotherapy Research

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Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Current therapeutic strategies are based on the use of Temozolomide (TMZ) and antihuman epidermal growth factor receptor (EGFR) drugs, such as Afatinib. However, clinically relevant drug‐resistance events are still present and closely related to a proinflammatory cancer brain microenvironment. The primary aim of this study is the association of Boswellic acid (BA), a molecule derived from Boswellia Serrata, with TMZ and Afatinibin different human GBM cells. We performed cell viability studies evaluating its antioxidant and anti‐inflammatory effects analyzing p65/NF‐κB and Leukotriene B4 expression and production of interleukins and growth factors (IL‐8, IL‐6, vascular endothelial growth factor, CXCL‐12, and MMP‐9). Considering the cardiotoxicity of TMZ and anti‐EGFR drugs, we evaluated the putative cardioprotective effects of BA in adult cardiomyocytes. BA significantly increased the anticancer activities of TMZ and Afatinib. These effects are related to its anti‐inflammatory and antioxidant effects, based on the inhibition of growth factors and proinflammatory interleukins. Notably, BA exerts also cardioprotective effects in combination to both drugs. This study provides evidences of anti‐inflammatory, cardioprotective, and chemo sensitizing effects of BA in glioblastoma cells giving a rationale for new translational studies based on the use of this natural molecule during conventional therapies.

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Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development

Cited by 144 publications

References 61 publications

Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope

Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope

Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

Boswellic acid has anti‐inflammatory effects and enhances the anticancer activities of Temozolomide and Afatinib, an irreversible ErbB family blocker, in human glioblastoma cells

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