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Robert Roskoski - One of the best experts on this subject based on the ideXlab platform.
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the ErbB her family of protein tyrosine kinases and cancer
Pharmacological Research, 2014Co-Authors: Robert RoskoskiAbstract: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.
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The ErbB/HER receptor protein-tyrosine kinases and cancer.
Biochemical and Biophysical Research Communications, 2004Co-Authors: Robert RoskoskiAbstract: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.
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the ErbB her receptor protein tyrosine kinases and cancer
Biochemical and Biophysical Research Communications, 2004Co-Authors: Robert RoskoskiAbstract: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.
Nancy E Hynes - One of the best experts on this subject based on the ideXlab platform.
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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, 2003Co-Authors: Thomas Holbro, Francisca Maurer, Roger R. Beerli, Magdalena Koziczak, Carlos F Barbas, Nancy E HynesAbstract: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.
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The ErbB receptors and their role in cancer progression.
Experimental Cell Research, 2003Co-Authors: Thomas Holbro, Gianluca Civenni, Nancy E HynesAbstract:The involvement of the ErbB receptor tyrosine kinases in human cancer, as well as their essential role in a variety of physiological events during normal development, have motivated the interest in this receptor family. Approaches taken to block the activity of ErbB receptors in cancer cells have not only proven that they drive in vitro tumor cell proliferation, but have also become clinically relevant for targeting tumors with deregulated ErbB signaling. The mechanisms and downstream effectors through which the ErbB receptors influence processes linked to malignant development, including proliferation, cell survival, angiogenesis, migration, and invasion, are, however, only now becoming apparent. Our particular emphasis in this review will be on how ErbB receptors, in particular ErbB1 and ErbB2, contribute to processes linked to cancer progression. Importantly, in keeping with the emerging theme that ErbB receptors do not function in isolation, we will focus on receptor cooperativity, i.e., ErbB1 cooperates with other classes of receptors, and the ligand-less ErbB2 functions as a heterodimer with other ErbBs.
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the efficacy of ErbB receptor targeted anticancer therapeutics is influenced by the availability of epidermal growth factor related peptides
Cancer Research, 2002Co-Authors: Andrea Barretto Motoyama, Nancy E Hynes, Heidi LaneAbstract: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.
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the ErbB signaling network receptor heterodimerization in development and cancer
The EMBO Journal, 2000Co-Authors: Monilola A. Olayioye, Heidi Lane, Richard M Neve, Nancy E HynesAbstract: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 …
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ErbB Receptor-induced Activation of Stat Transcription Factors Is Mediated by Src Tyrosine Kinases
Journal of Biological Chemistry, 1999Co-Authors: Monilola A. Olayioye, Kay Horsch, Iwan Beuvink, John M Daly, Nancy E HynesAbstract: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.
Peter H Odonnell - One of the best experts on this subject based on the ideXlab platform.
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afatinib activity in platinum refractory metastatic urothelial carcinoma in patients with ErbB alterations
Journal of Clinical Oncology, 2016Co-Authors: Noura Choudhury, Alexa Campanile, James L Wade, Tatjana Antic, Walter M Stadler, Yusuke Nakamura, Kai Lee Yap, Carrie Fitzpatrick, Theodore Karrison, Peter H OdonnellAbstract:PurposeSomatic mutations and copy number variation in the ErbB family are frequent in urothelial carcinoma (UC) and may represent viable therapeutic targets. We studied whether afatinib (an oral, irreversible inhibitor of the ErbB family) has activity in UC and if specific ErbB molecular alterations are associated with clinical response.Patients and MethodsIn this phase II trial, patients with metastatic platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance. The primary end point was 3-month progression-free survival (PFS3). Prespecified tumor analysis for alterations in EGFR, HER2, ErbB3, and ErbB4 was conducted.ResultsThe first-stage enrollment goal of 23 patients was met. Patient demographic data included: 78% male, median age 67 years (range, 36 to 82 years), hemoglobin < 10 g/dL in 17%, liver metastases in 30%, median time from prior chemotherapy of 3.6 months, and Eastern Cooperative Oncology Group performance status ≤ 1 in 100%. No unexpected toxicities we...
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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, 2015Co-Authors: Noura Choudhury, Alexa Campanile, James L Wade, Tatjana Antic, Walter M Stadler, Yusuke Nakamura, Peter H OdonnellAbstract: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...
Noura Choudhury - One of the best experts on this subject based on the ideXlab platform.
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afatinib activity in platinum refractory metastatic urothelial carcinoma in patients with ErbB alterations
Journal of Clinical Oncology, 2016Co-Authors: Noura Choudhury, Alexa Campanile, James L Wade, Tatjana Antic, Walter M Stadler, Yusuke Nakamura, Kai Lee Yap, Carrie Fitzpatrick, Theodore Karrison, Peter H OdonnellAbstract:PurposeSomatic mutations and copy number variation in the ErbB family are frequent in urothelial carcinoma (UC) and may represent viable therapeutic targets. We studied whether afatinib (an oral, irreversible inhibitor of the ErbB family) has activity in UC and if specific ErbB molecular alterations are associated with clinical response.Patients and MethodsIn this phase II trial, patients with metastatic platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance. The primary end point was 3-month progression-free survival (PFS3). Prespecified tumor analysis for alterations in EGFR, HER2, ErbB3, and ErbB4 was conducted.ResultsThe first-stage enrollment goal of 23 patients was met. Patient demographic data included: 78% male, median age 67 years (range, 36 to 82 years), hemoglobin < 10 g/dL in 17%, liver metastases in 30%, median time from prior chemotherapy of 3.6 months, and Eastern Cooperative Oncology Group performance status ≤ 1 in 100%. No unexpected toxicities we...
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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, 2015Co-Authors: Noura Choudhury, Alexa Campanile, James L Wade, Tatjana Antic, Walter M Stadler, Yusuke Nakamura, Peter H OdonnellAbstract: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...
Peter K Sorger - One of the best experts on this subject based on the ideXlab platform.
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rapid phospho turnover by receptor tyrosine kinases impacts downstream signaling and drug binding
Molecular Cell, 2011Co-Authors: Laura B Kleiman, Thomas Maiwald, Holger Conzelmann, Douglas A Lauffenburger, Peter K SorgerAbstract:Epidermal growth factor receptors (ErbB1–4) are oncogenic receptor tyrosine kinases (RTKs) that regulate diverse cellular processes. In this study, we combine measurement and mathematical modeling to quantify phospho-turnover at ErbB receptors in human cells and to determine the consequences for signaling and drug binding. We find that phosphotyrosine residues on ErbB1 have half-lives of a few seconds and therefore turn over 100–1000 times in the course of a typical immediate-early response to ligand. Rapid phospho-turnover is also observed for EGF-activated ErbB2 and ErbB3, unrelated RTKs, and multiple intracellular adaptor proteins and signaling kinases. Thus, the complexes formed on the cytoplasmic tail of active receptors and the downstream signaling kinases they control are highly dynamic and antagonized by potent phosphatases. We develop a kinetic scheme for binding of anti-ErbB1 drugs to receptors and show that rapid phospho-turnover significantly impacts their mechanisms of action.
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input output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data
Molecular Systems Biology, 2009Co-Authors: William W Chen, Birgit Schoeberl, Douglas A Lauffenburger, Paul J Jasper, Mario Niepel, Ulrik Nielsen, Peter K SorgerAbstract:The ErbB signaling pathways, which regulate diverse physiological responses such as cell survival, proliferation and motility, have been subjected to extensive molecular analysis. Nonetheless, it remains poorly understood how different ligands induce different responses and how this is affected by oncogenic mutations. To quantify signal flow through ErbB-activated pathways we have constructed, trained and analyzed a mass action model of immediate-early signaling involving ErbB1–4 receptors (EGFR, HER2/Neu2, ErbB3 and ErbB4), and the MAPK and PI3K/Akt cascades. We find that parameter sensitivity is strongly dependent on the feature (e.g. ERK or Akt activation) or condition (e.g. EGF or heregulin stimulation) under examination and that this context dependence is informative with respect to mechanisms of signal propagation. Modeling predicts log-linear amplification so that significant ERK and Akt activation is observed at ligand concentrations far below the Kd for receptor binding. However, MAPK and Akt modules isolated from the ErbB model continue to exhibit switch-like responses. Thus, key system-wide features of ErbB signaling arise from nonlinear interaction among signaling elements, the properties of which appear quite different in context and in isolation.