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  1. AU="Starr, Megan M"
  2. AU=Rajapaksa Shabna
  3. AU="Mohammed Aly Abdou" AU="Mohammed Aly Abdou"
  4. AU=Cooper Isabella D
  5. AU="Luis Rivera-Armenta, Jose"
  6. AU="Zahid Shaikh"
  7. AU="Scovil, Carol"
  8. AU="Grove, Nico"
  9. AU="McGuire, K J"
  10. AU="Martin, Bianca Aparecida"
  11. AU="Hampton, Joshua Trae"
  12. AU=Thesen Thomas
  13. AU=Oliveira Giuliano da Paz
  14. AU="García, Patricia J"
  15. AU="Hosseinpanah, Farhad"
  16. AU="Mayuni, Grace"
  17. AU="Volkova, Yulia L"
  18. AU="Dauwerse, Sierk"

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  1. Artikel ; Online: Corrigendum to: "Nuclear EGFR as a molecular target in cancer" [Radiother Oncol 108 (2013) 370-77].

    Brand, Toni M / Iida, Mari / Luthar, Neha / Starr, Megan M / Huppert, Evan J / Wheeler, Deric L

    Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

    2018  Band 130, Seite(n) 195

    Sprache Englisch
    Erscheinungsdatum 2018-11-13
    Erscheinungsland Ireland
    Dokumenttyp Published Erratum
    ZDB-ID 605646-5
    ISSN 1879-0887 ; 0167-8140
    ISSN (online) 1879-0887
    ISSN 0167-8140
    DOI 10.1016/j.radonc.2018.10.011
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Mapping C-terminal transactivation domains of the nuclear HER family receptor tyrosine kinase HER3.

    Brand, Toni M / Iida, Mari / Luthar, Neha / Wleklinski, Matthew J / Starr, Megan M / Wheeler, Deric L

    Publikation ZURÜCKGEZOGEN

    PloS one

    2013  Band 8, Heft 8, Seite(n) e71518

    Abstract: Nuclear localized HER family receptor tyrosine kinases (RTKs) have been observed in primary tumor specimens and cancer cell lines for nearly two decades. Inside the nucleus, HER family members (EGFR, HER2, and HER3) have been shown to function as co- ... ...

    Abstract Nuclear localized HER family receptor tyrosine kinases (RTKs) have been observed in primary tumor specimens and cancer cell lines for nearly two decades. Inside the nucleus, HER family members (EGFR, HER2, and HER3) have been shown to function as co-transcriptional activators for various cancer-promoting genes. However, the regions of each receptor that confer transcriptional potential remain poorly defined. The current study aimed to map the putative transactivation domains (TADs) of the HER3 receptor. To accomplish this goal, various intracellular regions of HER3 were fused to the DNA binding domain of the yeast transcription factor Gal4 (Gal4DBD) and tested for their ability to transactivate Gal4 UAS-luciferase. Results from these analyses demonstrated that the C-terminal domain of HER3 (CTD, amino acids distal to the tyrosine kinase domain) contained potent transactivation potential. Next, nine HER3-CTD truncation mutants were constructed to map minimal regions of transactivation potential using the Gal4 UAS-luciferase based system. These analyses identified a bipartite region of 34 (B₁) and 27 (B₂) amino acids in length that conferred the majority of HER3's transactivation potential. Next, we identified full-length nuclear HER3 association and regulation of a 122 bp region of the cyclin D1 promoter. To understand how the B₁ and B₂ regions influenced the transcriptional functions of nuclear HER3, we performed cyclin D1 promoter-luciferase assays in which HER3 deleted of the B₁ and B₂ regions was severely hindered in regulating this promoter. Further, the overexpression of HER3 enhanced cyclin D1 mRNA expression, while HER3 deleted of its identified TADs was hindered at doing so. Thus, the ability for HER3 to function as a transcriptional co-activator may be dependent on specific C-terminal TADs.
    Mesh-Begriff(e) Cell Line ; Cell Nucleus/ultrastructure ; Cyclin D1/analysis ; Cyclin D1/genetics ; Humans ; Mutation ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; Receptor, ErbB-3/analysis ; Receptor, ErbB-3/metabolism ; Transcriptional Activation
    Chemische Substanzen Cyclin D1 (136601-57-5) ; Receptor, ErbB-3 (EC 2.7.10.1)
    Sprache Englisch
    Erscheinungsdatum 2013-08-08
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Retracted Publication
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0071518
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Nuclear EGFR as a molecular target in cancer.

    Brand, Toni M / Iida, Mari / Luthar, Neha / Starr, Megan M / Huppert, Evan J / Wheeler, Deric L

    Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

    2013  Band 108, Heft 3, Seite(n) 370–377

    Abstract: The epidermal growth factor receptor (EGFR) has been one of the most targeted receptors in the field of oncology. While anti-EGFR inhibitors have demonstrated clinical success in specific cancers, most patients demonstrate either intrinsic or acquired ... ...

    Abstract The epidermal growth factor receptor (EGFR) has been one of the most targeted receptors in the field of oncology. While anti-EGFR inhibitors have demonstrated clinical success in specific cancers, most patients demonstrate either intrinsic or acquired resistance within one year of treatment. Many mechanisms of resistance to EGFR inhibitors have been identified, one of these being attributed to alternatively localized EGFR from the cell membrane into the cell's nucleus. Inside the nucleus, EGFR functions as a co-transcription factor for several genes involved in cell proliferation and angiogenesis, and as a tyrosine kinase to activate and stabilize proliferating cell nuclear antigen and DNA dependent protein kinase. Nuclear localized EGFR is highly associated with disease progression, worse overall survival in numerous cancers, and enhanced resistance to radiation, chemotherapy, and the anti-EGFR therapies gefitinib and cetuximab. In this review the current knowledge of how nuclear EGFR enhances resistance to cancer therapeutics is discussed, in addition to highlighting ways to target nuclear EGFR as an anti-cancer strategy in the future.
    Mesh-Begriff(e) Animals ; Celecoxib ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/physiology ; Humans ; Neoplasms/drug therapy ; Proliferating Cell Nuclear Antigen/physiology ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Pyrazoles/pharmacology ; Radiation Tolerance ; Sulfonamides/pharmacology
    Chemische Substanzen Proliferating Cell Nuclear Antigen ; Pyrazoles ; Sulfonamides ; ErbB Receptors (EC 2.7.10.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Celecoxib (JCX84Q7J1L)
    Sprache Englisch
    Erscheinungsdatum 2013-07-03
    Erscheinungsland Ireland
    Dokumenttyp Journal Article ; Review
    ZDB-ID 605646-5
    ISSN 1879-0887 ; 0167-8140
    ISSN (online) 1879-0887
    ISSN 0167-8140
    DOI 10.1016/j.radonc.2013.06.010
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Verfügbar in ZB MED Köln/Königswinter

    Zs.A 1926: Hefte anzeigen Standort:
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  4. Artikel ; Online: Targeting AKT with the allosteric AKT inhibitor MK-2206 in non-small cell lung cancer cells with acquired resistance to cetuximab.

    Iida, Mari / Brand, Toni M / Campbell, David A / Starr, Megan M / Luthar, Neha / Traynor, Anne M / Wheeler, Deric L

    Cancer biology & therapy

    2013  Band 14, Heft 6, Seite(n) 481–491

    Abstract: The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for use in oncology. Despite clinical success the majority of patients do not ... ...

    Abstract The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for use in oncology. Despite clinical success the majority of patients do not respond to cetuximab and those who initially respond frequently acquire resistance. To understand how tumor cells acquire resistance to cetuximab we developed a model of resistance using the non-small cell lung cancer line NCI-H226. We found that cetuximab-resistant (Ctx (R) ) clones manifested strong activation of EGFR, PI3K/AKT and MAPK. To investigate the role of AKT signaling in cetuximab resistance we analyzed the activation of the AKT pathway effector molecules using a human AKT phospho-antibody array. Strong activation was observed in Ctx (R) clones for several key AKT substrates including c-jun, GSK3β, eIF4E, rpS6, IKKα, IRS-1 and Raf1. Inhibition of AKT signaling by siAKT1/2 or by the allosteric AKT inhibitor MK-2206 resulted in robust inhibition of cell proliferation in all Ctx (R) clones. Moreover, the combinational treatment of cetuximab and MK-2206 resulted in further decreases in proliferation than either drug alone. This combinatorial treatment resulted in decreased activity of both AKT and MAPK thus highlighting the importance of simultaneous pathway inhibition to maximally affect the growth of Ctx (R) cells. Collectively, our findings demonstrate that AKT activation is an important pathway in acquired resistance to cetuximab and suggests that combinatorial therapy directed at both the AKT and EGFR/MAPK pathways may be beneficial in this setting.
    Mesh-Begriff(e) Allosteric Regulation ; Antibodies, Monoclonal, Humanized/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis ; Carcinoma, Non-Small-Cell Lung ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cetuximab ; Drug Evaluation, Preclinical ; Drug Resistance, Neoplasm ; Heterocyclic Compounds, 3-Ring/pharmacology ; Humans ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism
    Chemische Substanzen Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; Heterocyclic Compounds, 3-Ring ; MK 2206 ; AKT1 protein, human (EC 2.7.11.1) ; AKT2 protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Cetuximab (PQX0D8J21J)
    Sprache Englisch
    Erscheinungsdatum 2013-06-12
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2146305-0
    ISSN 1555-8576 ; 1538-4047
    ISSN (online) 1555-8576
    ISSN 1538-4047
    DOI 10.4161/cbt.24342
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Overcoming acquired resistance to cetuximab by dual targeting HER family receptors with antibody-based therapy.

    Iida, Mari / Brand, Toni M / Starr, Megan M / Huppert, Evan J / Luthar, Neha / Bahrar, Harsh / Coan, John P / Pearson, Hannah E / Salgia, Ravi / Wheeler, Deric L

    Molecular cancer

    2014  Band 13, Seite(n) 242

    Abstract: Background: Cetuximab, an anti-EGFR monoclonal antibody, is used to treat several cancers. However, many patients who initially respond to cetuximab acquire resistance. To examine mechanisms of acquired resistance, we developed a series of cetuximab- ... ...

    Abstract Background: Cetuximab, an anti-EGFR monoclonal antibody, is used to treat several cancers. However, many patients who initially respond to cetuximab acquire resistance. To examine mechanisms of acquired resistance, we developed a series of cetuximab-resistant (Ctx(R)) clones derived from the cetuximab sensitive (CtxS) non-small cell lung cancer (NSCLC) cell line H226. Previous studies characterizing this model revealed that: 1) EGFR was robustly overexpressed in Ctx(R) clones due to decreased EGFR ubiquitination and degradation and 2) Ctx(R) clones expressed increased HER2 and HER3 activation resulting in constitutive activation of the PI3K/AKT signaling axis. These findings suggest that dual targeting HER family receptors would be highly beneficial in the Ctx(R) setting.
    Results: Since HER3 has been implicated in resistance to EGFR inhibitors, the efficacy of dually targeting both EGFR and HER3 in Ctx(R) models was evaluated. First, EGFR and HER3 expression were knocked down with siRNAs. Compared to the Ctx(S) parental cell line (HP), all Ctx(R) clones exhibited robust decreases in cell proliferation upon dual knockdown. Analysis of Ctx(R) clones indicated that neuregulin-1 was highly overexpressed compared to HP cells. Incubation of HP cells with neuregulin-1 rendered them resistant to cetuximab. Next, dual treatment of Ctx(R) clones with cetuximab and the HER3 neutralizing monoclonal antibody (mAb) U3-1287 led to potent anti-proliferative effects. Blockade of EGFR with cetuximab resulted in inactivation of MAPK, while blockade of HER3 with U3-1287 resulted in the inactivation of AKT. Treatment with both mAbs resulted in knockdown of both signaling pathways simultaneously. HER2 was also strongly inactivated upon dual mAb therapy, suggesting that this treatment regimen can diminish signaling from three HER family receptors. De novo CtxR H226 mouse xenografts were established to determine if dual therapy could overcome acquired resistance to cetuximab in vivo. Tumors that had acquired resistance to cetuximab were significantly growth delayed upon dual treatment of U3-1287 and cetuximab compared to those continued on cetuximab only. Combinatorial-treated xenograft tumors expressed decreased Ki67 and increased cleaved caspase-3 levels compared to tumors treated with either monotherapy.
    Conclusions: These studies demonstrate that dually targeting HER family receptors with antibody-based therapies can overcome acquired resistance to cetuximab.
    Mesh-Begriff(e) Animals ; Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antibodies, Neutralizing ; Antineoplastic Agents/therapeutic use ; Broadly Neutralizing Antibodies ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cetuximab ; Drug Resistance, Neoplasm/drug effects ; ErbB Receptors/metabolism ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/metabolism ; Male ; Mice ; Mice, Nude ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, ErbB-2/metabolism ; Receptor, ErbB-3/metabolism ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays/methods
    Chemische Substanzen Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antibodies, Neutralizing ; Antineoplastic Agents ; Broadly Neutralizing Antibodies ; patritumab (86780VJI1Q) ; ERBB3 protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Receptor, ErbB-3 (EC 2.7.10.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Cetuximab (PQX0D8J21J)
    Sprache Englisch
    Erscheinungsdatum 2014-10-24
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1476-4598
    ISSN (online) 1476-4598
    DOI 10.1186/1476-4598-13-242
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Sym004, a novel EGFR antibody mixture, can overcome acquired resistance to cetuximab.

    Iida, Mari / Brand, Toni M / Starr, Megan M / Li, Chunrong / Huppert, Evan J / Luthar, Neha / Pedersen, Mikkel W / Horak, Ivan D / Kragh, Michael / Wheeler, Deric L

    Neoplasia (New York, N.Y.)

    2013  Band 15, Heft 10, Seite(n) 1196–1206

    Abstract: The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in a variety of human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for head and neck and colorectal cancer treatment, but many ... ...

    Abstract The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in a variety of human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for head and neck and colorectal cancer treatment, but many patients treated with cetuximab don't respond or eventually acquire resistance. To determine how tumor cells acquire resistance to cetuximab, we previously developed a model of acquired resistance using the non-small cell lung cancer line NCI-H226. These cetuximab-resistant (Ctx(R)) cells exhibit increased steady-state EGFR expression secondary to alterations in EGFR trafficking and degradation and, further, retained dependence on EGFR signaling for enhanced growth potential. Here, we examined Sym004, a novel mixture of antibodies directed against distinct epitopes on the extracellular domain of EGFR, as an alternative therapy for Ctx(R) tumor cells. Sym004 treatment of Ctx(R) clones resulted in rapid EGFR degradation, followed by robust inhibition of cell proliferation and down-regulation of several mitogen-activated protein kinase pathways. To determine whether Sym004 could have therapeutic benefit in vivo, we established de novo Ctx(R) NCI-H226 mouse xenografts and subsequently treated Ctx(R) tumors with Sym004. Sym004 treatment of mice harboring Ctx(R) tumors resulted in growth delay compared to mice continued on cetuximab. Levels of total and phospho-EGFR were robustly decreased in Ctx(R) tumors treated with Sym004. Immunohistochemical analysis of these Sym004-treated xenograft tumors further demonstrated decreased expression of Ki67, and phospho-rpS6, as well as a modest increase in cleaved caspase-3. These results indicate that Sym004 may be an effective targeted therapy for Ctx(R) tumors.
    Mesh-Begriff(e) Animals ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized/pharmacology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cetuximab ; Drug Resistance, Neoplasm/drug effects ; ErbB Receptors/immunology ; ErbB Receptors/metabolism ; Heterografts ; Humans ; MAP Kinase Signaling System ; Male ; Mice ; Mice, Nude
    Chemische Substanzen Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; futuximab (B37J680LX0) ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Cetuximab (PQX0D8J21J)
    Sprache Englisch
    Erscheinungsdatum 2013-10-30
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1483840-0
    ISSN 1476-5586 ; 1522-8002
    ISSN (online) 1476-5586
    ISSN 1522-8002
    DOI 10.1593/neo.131584
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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