The Experts below are selected from a list of 34131 Experts worldwide ranked by ideXlab platform

Nancy E Hynes - One of the best experts on this subject based on the ideXlab platform.

  • erbb1 and erbb2 have distinct functions in tumor cell invasion and intravasation
    Clinical Cancer Research, 2009
    Co-Authors: Dmitriy Kedrin, Nancy E Hynes, Jeffrey B. Wyckoff, Pamela Boimel, Salvatore J. Coniglio, Carlos L. Arteaga, Jeffrey E. Segall
    Abstract:

    Purpose: The epidermal growth factor receptor (ERBB1) and related family member HER-2/ neu (ERBB2) are often overexpressed in aggressive breast cancers and their overexpression is correlated with poor prognosis. Clinical studies using ERBB inhibitors have focused on tumor growth effects, but ERBBs can contribute to malignancy independent of their effects on tumor growth. Our studies were designed to evaluate the effect of ERBB inhibition on tumor cell motility and intravasation in vivo using clinically relevant small-molecule inhibitors. Experimental Design: Using in vivo mouse models of breast cancer, we test the effects of ERBB1 and ERBB2 inhibitors AC480 and lapatinib, ERBB1 inhibitor gefitinib, and ERBB2 inhibitor AG825 on in vivo tumor cell invasive properties in mammary fat pad tumors. Results: ERBB1 and ERBB2 inhibition rapidly (within 3 h) inhibits both tumor cell motility and intravasation. Using gefitinib, ERBB1 inhibition rapidly inhibits tumor cell motility and invasion but not intravasation, whereas ERBB2 inhibition by AG825 rapidly blocks intravasation. Conclusions: ERBB1 and ERBB2 inhibition can rapidly block tumor cell invasive properties. In addition, we differentiate for the first time the contributions of ERBB1 and ERBB2 to the key metastatic properties of in vivo tumor cell invasion and intravasation. These experiments temporally and molecularly separate two key stages in tumor cell entry into blood vessels: invasion and intravasation. These results indicate that ERBB inhibition should be considered for blocking other tumor cell malignant properties besides growth.

  • the erbb2 ERBB3 heterodimer functions as an oncogenic unit erbb2 requires ERBB3 to drive breast tumor cell proliferation
    Proceedings of the National Academy of Sciences of the United States of America, 2003
    Co-Authors: Thomas Holbro, Francisca Maurer, Roger R. Beerli, Magdalena Koziczak, Carlos F Barbas, Nancy E Hynes
    Abstract:

    ErbB2 is a receptor tyrosine kinase whose activity in normal cells depends on dimerization with another ligand-binding ErbB recep- tor. In contrast, amplification of c-erbB2 in tumors results in dramatic overexpression and constitutive activation of the recep- tor. Breast cancer cells overexpressing ErbB2 depend on its activity for proliferation, because treatment of these cells with ErbB2- specific antagonistic antibodies or kinase inhibitors blocks tumor cells in the G1 phase of the cell cycle. Intriguingly, loss of ErbB2 signaling is accompanied by a decrease in the phosphotyrosine content of ERBB3. On the basis of these results, it has been proposed that ERBB3 might be a partner for ErbB2 in promoting cellular transformation. To test this hypothesis and directly exam- ine the role of the ''kinase dead'' ERBB3, we specifically ablated its expression with a designer transcription factor (E3). By infection of ErbB2-overexpressing breast cancer cells with a retrovirus express- ing E3, we show that ERBB3 is an essential partner in the transfor- mation process. Loss of functional ErbB2 or ERBB3 has similar effects on cell proliferation and cell cycle regulators. Furthermore, expression of constitutively active protein kinase B rescues the proliferative block induced as a consequence of loss of ErbB2 or ERBB3 signaling. These results demonstrate that ErbB2 overexpres- sion and activity alone are insufficient to promote breast tumor cell division. Furthermore, we identify ERBB3's role, which is to couple active ErbB2 to the phosphatidylinositol 3-kinaseprotein kinase B pathway. Thus, the ErbB2ERBB3 dimer functions as an oncogenic unit to drive breast tumor cell proliferation.

  • the efficacy of erbb receptor targeted anticancer therapeutics is influenced by the availability of epidermal growth factor related peptides
    Cancer Research, 2002
    Co-Authors: Andrea Barretto Motoyama, Nancy E Hynes, Heidi Lane
    Abstract:

    The ErbB1 and ErbB2 receptor tyrosine kinases (RTKs) play important roles in the development of numerous types of human cancer and, as such, have been pursued as anticancer targets. To understand the mechanisms contributing to the response of tumor cells to receptor-directed therapeutics, the sensitivity of the ErbB receptor-overexpressing tumor cell lines BT474 and MKN7 to specific inhibitors has been examined. The inhibitors used included monoclonal antibody (mAb) 4D5, which targets ErbB2, and the small molecular weight kinase inhibitors CGP59326 and PKI166, which block the activity of ErbB1 or both ErbB1 and ErbB2, respectively. We had reported previously that although both BT474 and MKN7 cells overexpress ErbB2, only BT474 cells show an antiproliferative response to mAb 4D5 treatment. Here, we show that MKN7 cells, which also overexpress ErbB1, are sensitive to CGP59326, displaying a 60% decrease in their proliferation after treatment with this inhibitor. Most carcinomas express multiple ErbB receptors as well as EGF-related ligands, a situation favoring activation of numerous combinations of ligand-activated receptors. Considering this, the sensitivity of MKN7 and BT474 cells to CGP59326 and mAb 4D5, respectively, was also tested in the presence of exogenous ligands. Treatment of MKN7 cells with CGP59326 in the presence of heregulin (HRG), which activates ErbB2/ERBB3, attenuated the antiproliferative effect of CGP59326 by 50%; MKN7 cells engineered to overexpress ERBB3 were completely rescued from CGP59326 by HRG. Likewise, BT474 cells treated with mAb 4D5 in the presence of epidermal growth factor, betacellulin, and HRG were rescued from its antiproliferative effects by 57, 84, and 90%, respectively. In both MKN7 and BT474 tumor cells, the degree of ligand-induced rescue from the inhibitors correlated with the potency of ErbB receptor activation and stimulation of the PI3K and MAPK intracellular signaling pathways. In comparison with the monospecific agents, treatment with the bispecific ErbB1/ErbB2 kinase inhibitor PKI166 almost completely prevented the EGF-related ligand-induced bypass of the proliferation block in the MKN7 and BT474 cells. These data suggest that the efficacy of anticancer drugs that block a single ErbB receptor may be compromised by the presence of exogenous epidermal growth factor-related ligands, a phenomenon that could be averted by simultaneously blocking multiple ErbB receptors.

  • the erbb signaling network receptor heterodimerization in development and cancer
    The EMBO Journal, 2000
    Co-Authors: Monilola A. Olayioye, Heidi Lane, Richard M Neve, Nancy E Hynes
    Abstract:

    Cells are continuously exposed to diverse stimuli ranging from soluble endocrine and paracrine factors, to signaling molecules on neighboring cells. It is of great importance that these extracellular signals are correctly interpreted by the cell, in order to achieve an appropriate developmental or proliferative response. Receptors of the tyrosine kinase family play pivotal roles in this process. By binding to specific peptide ligands they are able to integrate these external stimuli with internal signal transduction pathways, contributing in this fashion to the ability of the cell to respond correctly to its environment. In this review, we will concentrate on the role of ErbB receptors as normal signal transducers and their contribution to the process of malignant transformation during tumor development. ErbB proteins belong to subclass I of the superfamily of receptor tyrosine kinases (RTKs). There are four members of the ErbB family: epidermal growth factor (EGF) receptor (also termed ErbB1/HER1), ErbB2/Neu/HER2, ERBB3/HER3 and ErbB4/HER4. We will refer to them, henceforth, as the ErbB receptors. All family members have in common an extracellular ligand‐binding domain, a single membrane‐spanning region and a cytoplasmic protein tyrosine kinase domain. A family of ligands, the EGF‐related peptide growth factors, bind the extracellular domain of ErbB receptors leading to the formation of both homo‐ and heterodimers. Dimerization consequently stimulates the intrinsic tyrosine kinase activity of the receptors and triggers autophosphorylation of specific tyrosine residues within the cytoplasmic domain. These phosphorylated residues serve as docking sites for signaling molecules involved in the regulation of intracellular signaling cascades. Ultimately, downstream effects on gene expression determine the biological response to receptor activation. ErbB receptors are expressed in a variety of tissues of epithelial, mesenchymal and neuronal origin, where they play fundamental roles in development, proliferation and differentiation. Moreover, deregulated expression of ErbB receptors, in particular ErbB1 and ErbB2, has …

  • ErbB Receptor-induced Activation of Stat Transcription Factors Is Mediated by Src Tyrosine Kinases
    Journal of Biological Chemistry, 1999
    Co-Authors: Monilola A. Olayioye, Kay Horsch, Iwan Beuvink, John M Daly, Nancy E Hynes
    Abstract:

    Abstract Epidermal growth factor (EGF) binding to its receptor, ErbB1, triggers various signal transduction pathways, one of which leads to the activation of signal transducer and activator of transcription (Stat) factors. The mechanism underlying ErbB1-induced Stat activation and whether Stats are downstream targets of other ErbB receptors have not been explored. In this report we show that ErbB2, ERBB3, and ErbB4 do not potentiate Stat5 phosphorylation by EGF. However, neu differentiation factor-induced heterodimers of ErbB2 and ErbB4 activated Stat5. In A431 cells, Stat1, Stat3, and Stat5, were constitutively complexed with ErbB1 and rapidly phosphorylated on tyrosine in response to EGF. Neither mutation of the conserved tyrosine residue (Tyr694) nor inactivation of the Stat5a SH2 domain disrupted this association. However, an intact SH2 domain was necessary for EGF-induced Stat5a phosphorylation. In contrast to prolactin, which induced only Tyr694 phosphorylation of Stat5a, EGF promoted phosphorylation on Tyr694 and additional tyrosine residue(s). Janus kinases (Jaks) were also constitutively associated with ErbB receptors and were phosphorylated in response to EGF-related ligands. However, we provide evidence that EGF- and neu differentiation factor-induced Stat activation are dependent on Src but not Jak kinases. Upon EGF stimulation, c-Src was rapidly recruited to Stat/ErbB receptor complexes. Pharmacological Src kinase inhibitors and a dominant negative c-Src ablated both Stat and Jak tyrosine phosphorylation. However, dominant negative Jaks did not affect EGF-induced Stat phosphorylation. Taken together, the experiments establish two independent roles for Src kinases: (i) key molecules in ErbB receptor-mediated Stat signaling and (ii) potential upstream regulators of Jak kinases.

Robert Roskoski - One of the best experts on this subject based on the ideXlab platform.

  • small molecule inhibitors targeting the egfr erbb family of protein tyrosine kinases in human cancers
    Pharmacological Research, 2019
    Co-Authors: Robert Roskoski
    Abstract:

    The EGFR family is among the most investigated receptor protein-tyrosine kinase groups owing to its general role in signal transduction and in oncogenesis. This family consists of four members that belong to the ErbB lineage of proteins (ErbB1-4). The ErbB proteins function as homo and heterodimers. These receptors contain an extracellular domain that consists of four parts: domains I and III are leucine-rich segments that participate in growth factor binding (except for ErbB2) and domains II and IV contain multiple disulfide bonds. Moreover, domain II participates in both homo and heterodimer formation within the ErbB/HER family of proteins. Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor-α, none bind to ErbB2, two bind to ERBB3, and seven ligands bind to ErbB4. The extracellular domain is followed by a single transmembrane segment of about 25 amino acid residues and an intracellular portion of about 550 amino acid residues that contains (i) a short juxtamembrane segment, (ii) a protein kinase domain, and (iii) a carboxyterminal tail. ErbB2 lacks a known activating ligand and ERBB3 is kinase impaired. Surprisingly, the ErbB2-ERBB3 heterodimer complex is the most active dimer in the family. These receptors are implicated in the pathogenesis of a large proportion of lung and breast cancers, which rank first and second, respectively, in the incidence of all types of cancers (excluding skin) worldwide. On the order of 20% of non-small cell lung cancers bear activating mutations in EGFR. More than 90% of these patients have exon-19 deletions (746ELREA750) or the exon-21 L858R substitution. Gefitinib and erlotinib are orally effective type I reversible EGFR mutant inhibitors; type I inhibitors bind to an active enzyme conformation. Unfortunately, secondary resistance to these drugs occurs within about one year owing to a T790M gatekeeper mutation. Osimertinib is an irreversible type VI inhibitor that forms a covalent bond with C797 of EGFR and is FDA-approved for the treatment of patients with this mutation; type VI inhibitors generally form a covalent adduct with their target protein. Resistance also develops to this and related type VI inhibitory drugs owing to a C797S mutation; the serine residue is unable to react with the drugs to form a covalent bond. Approximately 20% of breast cancer patients exhibit ErbB2/HER2 gene amplification on chromosome 17q. One of the earliest targeted treatments in cancer involved the development of trastuzumab, a monoclonal antibody that interacts with the extracellular domain ErbB2/HER2 causing its down regulation. Surgery, radiation therapy, chemotherapy with cytotoxic drugs, and hormonal modulation are the mainstays in the treatment of breast cancer. Moreover, lapatinib and neratinib are FDA-approved small molecule ErbB2/HER2 antagonists used in the treatment of selected breast cancer patients. Of the approximate three dozen FDA-approved small molecule protein kinase inhibitors, five are type VI irreversible inhibitors and four of them including afatinib, osimertinib, dacomitinib, and neratinib are directed against the ErbB family of receptors (ibrutinib is the fifth and it targets Bruton tyrosine kinase). Avitinib, olmutinib, and pelitinib are additional type VI inhibitors in clinical trials for non-small cell lung cancer that target EGFR. Secondary resistance to both targeted and cytotoxic drugs is the norm, and devising and implementing strategies for minimizing or overcoming resistance is an important goal in cancer therapeutics.

  • the erbb her family of protein tyrosine kinases and cancer
    Pharmacological Research, 2014
    Co-Authors: Robert Roskoski
    Abstract:

    Abstract The human epidermal growth factor receptor (EGFR) family consists of four members that belong to the ErbB lineage of proteins (ErbB1–4). These receptors consist of a glycosylated extracellular domain, a single hydrophobic transmembrane segment, and an intracellular portion with a juxtamembrane segment, a protein kinase domain, and a carboxyterminal tail. Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor α, none bind to ErbB2, two bind to ERBB3, and seven ligands bind to ErbB4. The ErbB proteins function as homo and heterodimers. The heterodimer consisting of ErbB2, which lacks a ligand, and ERBB3, which is kinase impaired, is surprisingly the most robust signaling complex of the ErbB family. Growth factor binding to EGFR induces a large conformational change in the extracellular domain, which leads to the exposure of a dimerization arm in domain II of the extracellular segment. Two ligand-EGFR complexes unite to form a back-to-back dimer in which the ligands are on opposite sides of the aggregate. Following ligand binding, EGFR intracellular kinase domains form an asymmetric homodimer that resembles the heterodimer formed by cyclin and cyclin-dependent kinase. The carboxyterminal lobe of the activator kinase of the dimer interacts with the amino-terminal lobe of the receiver kinase thereby leading to its allosteric stimulation. Downstream ErbB signaling modules include the phosphatidylinositol 3-kinase/Akt (PKB) pathway, the Ras/Raf/MEK/ERK1/2 pathway, and the phospholipase C (PLCγ) pathway. Several malignancies are associated with the mutation or increased expression of members of the ErbB family including lung, breast, stomach, colorectal, head and neck, and pancreatic carcinomas and glioblastoma (a brain tumor). Gefitinib, erlotinib, and afatinib are orally effective protein-kinase targeted quinazoline derivatives that are used in the treatment of ERBB1-mutant lung cancer. Lapatinib is an orally effective quinazoline derivative used in the treatment of ErbB2-overexpressing breast cancer. Trastuzumab, pertuzumab, and ado-trastuzumab emtansine, which are given intravenously, are monoclonal antibodies that target the extracellular domain and are used for the treatment of ErbB2-positive breast cancer; ado-trastuzumab emtansine is an antibody-drug conjugate that delivers a cytotoxic drug to cells overexpressing ErbB2. Cetuximab and panitumumab are monoclonal antibodies that target ErbB1 and are used in the treatment of colorectal cancer. Cancers treated with these targeted drugs eventually become resistant to them. The role of combinations of targeted drugs or targeted drugs with cytotoxic therapies is being explored in an effort to prevent or delay drug resistance in the treatment of these malignancies.

  • the erbb her receptor protein tyrosine kinases and cancer
    Biochemical and Biophysical Research Communications, 2004
    Co-Authors: Robert Roskoski
    Abstract:

    Abstract The ErbB/HER protein-tyrosine kinases, which include the epidermal growth factor receptor, consist of a growth-factor-binding ectodomain, a single transmembrane segment, an intracellular protein-tyrosine kinase catalytic domain, and a tyrosine-containing cytoplasmic tail. The genes for the four members of this family, ErbB1–ErbB4, are found on different human chromosomes. Null mutations of any of the ErbB family members result in embryonic lethality. ErbB1 and ErbB2 are overexpressed in a wide variety of tumors including breast, colorectal, ovarian, and non-small cell lung cancers. The structures of the ectodomains of the ErbB receptors in their active and inactive conformation have shed light on the mechanism of receptor activation. The extracellular component of the ErbB proteins consists of domains I–IV. The activating growth factor, which binds to domains I and III, selects and stabilizes a conformation that allows a dimerization arm to extend from domain II to interact with an ErbB dimer partner. As a result of dimerization, protein kinase activation, trans-autophosphorylation, and initiation of signaling occur. The conversion of the inactive to active receptor involves a major rotation of the ectodomain. The ErbB receptors are targets for anticancer drugs. Two strategies for blocking the action of these proteins include antibodies directed against the ectodomain and drugs that inhibit protein-tyrosine kinase activity. A reversible ATP competitive inhibitor of ErbB1 (ZD1839, or Iressa) and an ErbB1 ectodomain directed antibody (IMC-C225, or Erbitux) have been approved for the treatment of non-small cell lung cancer and colorectal cancer, respectively. An ErbB2/HER2 ectodomain directed antibody (trastuzumab, or Herceptin) has also been approved for the treatment of breast cancer. Current research promises to produce additional agents based upon these approaches.

Peter H Odonnell - One of the best experts on this subject based on the ideXlab platform.

  • afatinib activity in platinum refractory metastatic urothelial carcinoma uc patients with erbb alterations results of a phase ii trial
    Journal of Clinical Oncology, 2016
    Co-Authors: Noura Choudhury, Alexa Campanile, James L Wade, Tatjana Antic, Walter M Stadler, Yusuke Nakamura, Peter H Odonnell
    Abstract:

    459 Background: Metastatic UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ERBB3 are frequent in UC and may represent viable therapeutic targets. We studied whether afatinib, an oral, irreversible Erb family blocker, has activity in UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance.The primary endpoint was 3-mo progression-free survival (PFS3) using a Simon two-stage design, with the trial proceeding to stage II if ≥ 30% pts in stage I had PFS3. Pre-specified analysis for EGFR, HER2, ERBB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman) of available archival tumor tissue. Results: The initial enrollment goal of 23 ptswas met: 18 M/5 F, median age 67 (36-82), ECOG 0 in 26%/1 in 74%, Hb < 10 g/dl in 17%, liver me...

  • association of her2 and ERBB3 molecular alterations with afatinib sensitivity in platinum refractory metastatic urothelial carcinoma uc in a phase ii trial
    Journal of Clinical Oncology, 2015
    Co-Authors: Noura Choudhury, Alexa Campanile, James L Wade, Tatjana Antic, Walter M Stadler, Yusuke Nakamura, Peter H Odonnell
    Abstract:

    312 Background: Platinum-refractory UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ERBB3 are frequent in UC and may represent viable targets for novel therapies. We aimed to investigate whether afatinib, an oral, irreversible Erb family blocker, has clinical benefit in metastatic UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC who received ≤1 chemotherapy in the metastatic setting received afatinib 40 mg/day continuously until disease progression or intolerable toxicity.Primary endpoint was 3-month progression-free survival (PFS3), with drug deemed promising if ≥42% pts had PFS3. Pre-specified analysis for EGFR, HER2, ERBB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman). Results: 15 ptshave enrolled: median age 66 (44-78), 11 M/4 F, ECOG PS 0 in 20%, PS 1 in 80%, Hb<10 g/dl in 20...

Mark A Lemmon - One of the best experts on this subject based on the ideXlab platform.

  • erbb2 resembles an autoinhibited invertebrate epidermal growth factor receptor
    Nature, 2009
    Co-Authors: Diego Alvarado, Daryl E Klein, Mark A Lemmon
    Abstract:

    The tyrosine kinase receptor ErbB2/HER2 has been implicated in cancer, in particular in breast cancer. It has been suggested that ErbB2 is constitutively activated as it lacks the extracellular tether that keeps other EGF receptor family members inactive unless they are occupied by ligand. However, Alvarado et al. now present evidence for an alternative mechanism of autoinhibition that keeps the only family member in Drosophila, dEGFR, inactive. dEGFR is most closely related to ErbB2, and the autoinhibitory interactions found in dEGFR are conserved in ErbB2, which has implications for approaches to therapeutically target ErbB2. The tyrosine kinase receptor ErbB2 has been implicated in cancer, particularly breast cancer. It has been suggested that its oncogenic signalling properties result from the absence of a key 'tether' in the extracellular region that autoinhibits other human ErbB receptors. ErbB2 is now shown to be the closest structural relative of the dEGFR receptor in Drosophila; although dEGFR also lacks a tether, a distinct set of autoinhibitory interactions keep it inactive. The orphan receptor tyrosine kinase ErbB2 (also known as HER2 or Neu) transforms cells when overexpressed1, and it is an important therapeutic target in human cancer2,3. Structural studies4,5 have suggested that the oncogenic (and ligand-independent) signalling properties of ErbB2 result from the absence of a key intramolecular ‘tether’ in the extracellular region that autoinhibits other human ErbB receptors, including the epidermal growth factor (EGF) receptor6. Although ErbB2 is unique among the four human ErbB receptors6,7, here we show that it is the closest structural relative of the single EGF receptor family member in Drosophila melanogaster (dEGFR). Genetic and biochemical data show that dEGFR is tightly regulated by growth factor ligands8, yet a crystal structure shows that it, too, lacks the intramolecular tether seen in human EGFR, ERBB3 and ErbB4. Instead, a distinct set of autoinhibitory interdomain interactions hold unliganded dEGFR in an inactive state. All of these interactions are maintained (and even extended) in ErbB2, arguing against the suggestion that ErbB2 lacks autoinhibition. We therefore suggest that normal and pathogenic ErbB2 signalling may be regulated by ligands in the same way as dEGFR. Our findings have important implications for ErbB2 regulation in human cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor.

  • the single transmembrane domains of erbb receptors self associate in cell membranes
    Journal of Biological Chemistry, 2002
    Co-Authors: Jeannine M Mendrola, Mitchell B Berger, Megan C King, Mark A Lemmon
    Abstract:

    Members of the epidermal growth factor receptor, or ErbB, family of receptor tyrosine kinases have a single transmembrane (TM) alpha-helix that is usually assumed to play a passive role in ligand-induced dimerization and activation of the receptor. However, recent studies with the epidermal growth factor receptor (ErbB1) and the erythropoietin receptor have indicated that interactions between TM alpha-helices do contribute to stabilization of ligand-independent and/or ligand-induced receptor dimers. In addition, not all of the expected ErbB receptor ligand-induced dimerization events can be recapitulated using isolated extracellular domains, suggesting that other regions of the receptor, such as the TM domain, may contribute to dimerization in vivo. Using an approach for analyzing TM domain interactions in Escherichia coli cell membranes, named TOXCAT, we find that the TM domains of ErbB receptors self-associate strongly in the absence of their extracellular domains, with the rank order ErbB4-TM > ErbB1-TM equivalent to ErbB2-TM > ERBB3-TM. A limited mutational analysis suggests that dimerization of these TM domains involves one or more GXXXG motifs, which occur frequently in the TM domains of receptor tyrosine kinases and are critical for stabilizing the glycophorin A TM domain dimer. We also analyzed the effect of the valine to glutamic acid mutation in ErbB2 that constitutively activates this receptor. Contrary to our expectations, this mutation reduced rather than increased ErbB2-TM dimerization. Our findings suggest a role for TM domain interactions in ErbB receptor function, possibly in stabilizing inactive ligand-independent receptor dimers that have been observed by several groups.

Noura Choudhury - One of the best experts on this subject based on the ideXlab platform.

  • afatinib activity in platinum refractory metastatic urothelial carcinoma uc patients with erbb alterations results of a phase ii trial
    Journal of Clinical Oncology, 2016
    Co-Authors: Noura Choudhury, Alexa Campanile, James L Wade, Tatjana Antic, Walter M Stadler, Yusuke Nakamura, Peter H Odonnell
    Abstract:

    459 Background: Metastatic UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ERBB3 are frequent in UC and may represent viable therapeutic targets. We studied whether afatinib, an oral, irreversible Erb family blocker, has activity in UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance.The primary endpoint was 3-mo progression-free survival (PFS3) using a Simon two-stage design, with the trial proceeding to stage II if ≥ 30% pts in stage I had PFS3. Pre-specified analysis for EGFR, HER2, ERBB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman) of available archival tumor tissue. Results: The initial enrollment goal of 23 ptswas met: 18 M/5 F, median age 67 (36-82), ECOG 0 in 26%/1 in 74%, Hb < 10 g/dl in 17%, liver me...

  • association of her2 and ERBB3 molecular alterations with afatinib sensitivity in platinum refractory metastatic urothelial carcinoma uc in a phase ii trial
    Journal of Clinical Oncology, 2015
    Co-Authors: Noura Choudhury, Alexa Campanile, James L Wade, Tatjana Antic, Walter M Stadler, Yusuke Nakamura, Peter H Odonnell
    Abstract:

    312 Background: Platinum-refractory UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ERBB3 are frequent in UC and may represent viable targets for novel therapies. We aimed to investigate whether afatinib, an oral, irreversible Erb family blocker, has clinical benefit in metastatic UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC who received ≤1 chemotherapy in the metastatic setting received afatinib 40 mg/day continuously until disease progression or intolerable toxicity.Primary endpoint was 3-month progression-free survival (PFS3), with drug deemed promising if ≥42% pts had PFS3. Pre-specified analysis for EGFR, HER2, ERBB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman). Results: 15 ptshave enrolled: median age 66 (44-78), 11 M/4 F, ECOG PS 0 in 20%, PS 1 in 80%, Hb<10 g/dl in 20...