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https://www.readbyqxmd.com/read/27913862/prognostic-impact-of-her3-based-on-protein-and-mrna-expression-in-high-grade-serous-ovarian-carcinoma
#1
Ulrike Unger, Carsten Denkert, Ioana Braicu, Jalid Sehouli, Manfred Dietel, Sibylle Loibl, Silvia Darb-Esfahani
HER3 is a member of the epidermal growth factor family and was predominantly described as a negative prognostic factor in various solid tumors as well as in ovarian cancer. In this study, we investigated HER3 on protein and mRNA expression in histologically defined subtypes of ovarian cancer looking for an influence on patient's survival. Altogether, we examined HER3 in ovarian high-grade serous (HGSC, n = 320), low-grade serous (LGSC, n = 55), endometrioid (EC, n = 33), and clear cell (CCC, n = 48) carcinomas using immunohistochemistry (IHC) and quantitative real-time reverse transcription PCR (qRT-PCR)...
December 2, 2016: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/27903463/her2-transmembrane-mutations-v659-g660-that-stabilize-homo-and-hetero-dimerization-are-rare-oncogenic-drivers-in-lung-adenocarcinoma-that-respond-to-afatinib
#2
Sai-Hong Ignatius Ou, Alexa B Schrock, Eduard V Bocharov, Samuel J Klempner, Carolina Kawamura Haddad, Gary Steinecker, Melissa Johnson, Barbara J Gitlitz, Jon Chung, Paulo V Campregher, Jeffrey S Ross, Philip J Stephens, Vincent A Miller, James H Suh, Siraj M Ali, Vamsidhar Velcheti
INTRODUCTION: HER2 transmembrane domain (TMD) mutations (HER2(V659E), HER2(G660D)) have previously been identified in lung adenocarcinomas, but their frequency and clinical significance is unknown. METHODS: We prospectively analyzed 8,551 consecutive lung adenocarcinomas using hybrid-capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians for the purpose of making therapy decisions. RESULTS: We identified 15 cases (0...
November 26, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27893711/the-induction-of-mig6-under-hypoxic-conditions-is-critical-for-dormancy-in-primary-cultured-lung-cancer-cells-with-activating-egfr-mutations
#3
H Endo, J Okami, H Okuyama, Y Nishizawa, F Imamura, M Inoue
The biologic activity of individual cancer cells is highly heterogeneous. Hypoxia, one of the prominent features of a tumor microenvironment, is thought to be causal in generating this cellular heterogeneity. In this study, we revealed that primary lung cancer cells harboring activating epidermal growth factor receptor (EGFR) mutations generally entered a dormant state when hypoxic. We found that heterodimer formation of the ERBB family receptor tyrosine kinases (RTKs), and their subsequent downstream signaling, was diminished under hypoxic conditions, although phosphorylation of the EGFR was retained...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27887869/a-highly-diverse-and-functional-na%C3%A3-ve-ubiquitin-variant-library-for-generation-of-intracellular-affinity-reagents
#4
Isabel Leung, Nick Jarvik, Sachdev Sidhu
We report the design, construction and validation of a highly diverse phage-displayed naïve ubiquitin variant (Ubv) library. We first conducted a mutation tolerance scan of 27 residues and confirmed that 24 of these could be substituted by chemically diverse amino acids without compromising the display of Ubvs on phage. Subsequently, we constructed a library containing 6.8×10(10) unique members in which these 24 positions were diversified with a degenerate codon that encodes for six amino acids that are prevalent in protein interaction sites...
November 22, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27872189/biophysical-evidence-for-intrinsic-disorder-in-the-c-terminal-tails-of-the-egfr-and-her3-receptor-tyrosine-kinases
#5
Theodore R Keppel, Kwabena Sarpong, Elisa M Murray, John Monsey, Jian Zhu, Ron Bose
The EGFR/ErbB family of receptor tyrosine kinases includes oncogenes important in the progression of breast and other cancers and they are targets for many drug development strategies. Each member of the ErbB family possesses a unique, structurally uncharacterized C-terminal tail that plays an important role in autophosphorylation and signal propagation. To determine if these C-terminal tails are intrinsically disordered regions, we conducted a battery of biophysical experiments on the EGFR and HER3 tails. Using hydrogen/deuterium exchange mass spectrometry, we measured the conformational dynamics of intracellular half constructs and compared the tails to the ordered kinase domains...
November 21, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27871278/the-prognostic-significance-of-human-epidermal-growth-factor-receptor-family-protein-expression-in-operable-pancreatic-cancer-her1-4-protein-expression-and-prognosis-in-pancreatic-cancer
#6
Qin Li, Lei Zhang, XiuHong Li, Han Yan, Liuting Yang, Yingying Li, Teng Li, Jing Wang, Bangwei Cao
BACKGROUND: Prognostic factors aid in the stratification and treatment of cancer. This study evaluated the prognostic significance of human epidermal growth factor receptor (HER) family members (HER1-4) expression in patients with operable pancreatic cancer. METHODS: The expression of individual HER proteins in patient tissue specimens was detected by immunohistochemistry staining. Patient follow-up time was between 1.0 and 78.1 months. RESULTS: Positive expression of HER1, HER2, HER3 and HER4 was detected in 41...
November 21, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27853996/a-phase-1-study-combining-the-her3-antibody-seribantumab-mm-121-and-cetuximab-with-and-without-irinotecan
#7
James M Cleary, Autumn J McRee, Geoffrey I Shapiro, Sara M Tolaney, Bert H O'Neil, Jeffrey D Kearns, Sara Mathews, Rachel Nering, Gavin MacBeath, Akos Czibere, Sunil Sharma, W Michael Korn
Background HER3/EGFR heterodimers have been implicated as a mode of resistance to EGFR-directed therapies. Methods This Phase 1 trial assessed the tolerability, maximum tolerated dose (MTD) and pharmacokinetic (PK) properties of the HER-3 antibody seribantumab in combination with cetuximab (Part I) or cetuximab and irinotecan (Part II) in patients with EGFR-dependent cancers. In Part I, escalating doses of seribantumab and cetuximab were administered. In Part II of the trial, escalating doses of seribantumab/cetuximab were combined with irinotecan 180 mg/m2 administered every two weeks...
November 16, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27844328/molecular-profiling-of-thymoma-and-thymic-carcinoma-genetic-differences-and-potential-novel-therapeutic-targets
#8
Franz Enkner, Bettina Pichlhöfer, Alexandru Teodor Zaharie, Milica Krunic, Tina Maria Holper, Stefan Janik, Bernhard Moser, Karin Schlangen, Barbara Neudert, Karin Walter, Brigitte Migschitz, Leonhard Müllauer
Thymoma and thymic carcinoma are thymic epithelial tumors (TETs). We performed a molecular profiling to investigate the pathogenesis of TETs and identify novel targets for therapy. We analyzed 37 thymomas (18 type A, 19 type B3) and 35 thymic carcinomas. The sequencing of 50 genes detected nonsynonymous mutations in 16 carcinomas affecting ALK, ATM, CDKN2A, ERBB4, FGFR3, KIT, NRAS and TP53. Only two B3 thymomas had a mutation in noncoding regions of the SMARCB1 and STK11 gene respectively. Three type A thymomas harbored a nonsynonymous HRAS mutation...
November 14, 2016: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/27843803/randomized-phase-ii-study-of-duligotuzumab-mehd7945a-vs-cetuximab-in-squamous-cell-carcinoma-of-the-head-and-neck-mehgan-study
#9
Jérôme Fayette, Lori Wirth, Cristina Oprean, Anghel Udrea, Antonio Jimeno, Danny Rischin, Christopher Nutting, Paul M Harari, Tibor Csoszi, Dana Cernea, Paul O'Brien, William D Hanley, Amy V Kapp, Maria Anderson, Elicia Penuel, Bruce McCall, Andrea Pirzkall, Jan B Vermorken
BACKGROUND: Duligotuzumab, a novel dual-action humanized IgG1 antibody that blocks ligand binding to epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody-dependent cell-mediated cytotoxicity. High tumor-expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab. METHODS: This multicenter, open-label, randomized phase II study (MEHGAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy and among patients with NRG1-high tumors...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27793840/targeting-of-pyk2-synergizes-with-egfr-antagonists-in-basal-like-tnbc-and-circumvents-her3-associated-resistance-via-the-nedd4-ndrg1-axis
#10
Nandini Verma, Anna-Katharina Müller, Charu Kothari, Effrosini Panayotopoulou, Amir Kedan, Michael Selitrennik, Gordon B Mills, Lan K Nguyen, Sungyoung Shin, Thomas Karn, Uwe Holtrich, Sima Lev
Triple negative breast cancer (TNBC) is a highly aggressive, heterogeneous disease with poor prognosis and no effective targeted therapies. EGFR is highly expressed in basal-like TNBC and considered as a potential therapeutic target. However, EGFR targeting exerts only marginal clinical benefits, possibly due to activation of compensatory signaling pathways, which are frequently associated with HER3 upregulation. Here we show that concomitant targeting of EGFR and the non-receptor tyrosine kinases PYK2/FAK synergistically inhibits the proliferation of basal-like TNBC cells in vitro and attenuates tumor growth in mouse xenograft model...
October 28, 2016: Cancer Research
https://www.readbyqxmd.com/read/27787520/increased-expression-of-ehf-via-gene-amplification-contributes-to-the-activation-of-her-family-signaling-and-associates-with-poor-survival-in-gastric-cancer
#11
Jing Shi, Yiping Qu, Xinru Li, Fang Sui, Demao Yao, Qi Yang, Bingyin Shi, Meiju Ji, Peng Hou
The biological function of E26 transformation-specific (ETS) transcription factor EHF/ESE-3 in human cancers remains largely unknown, particularly gastric cancer. The aim of this study was to explore the role of EHF in tumorigenesis and its potential as a therapeutic target in gastric cancer. By using quantitative RT-PCR (qRT-PCR), immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, we investigated the expression and copy number of EHF in a cohort of gastric cancers and control subjects...
October 27, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27776352/the-impact-of-erbb-family-germline-single-nucleotide-polymorphisms-on-survival-response-to-adjuvant-trastuzumab-treatment-in-her2-positive-breast-cancer
#12
Sinead Toomey, Stephen F Madden, Simon J Furney, Yue Fan, Mark McCormack, Carragh Stapleton, Mattia Cremona, Gianpiero L Cavalleri, Malgorzata Milewska, Naomi Elster, Aoife Carr, Joanna Fay, Elaine W Kay, Susan Kennedy, John Crown, William M Gallagher, Bryan T Hennessy, Alex J Eustace
BACKGROUND: Trastuzumab treatment for women with HER2-positive breast cancer (BC) resulted in the significant improvement of both relapse free survival (RFS) and overall survival (OS). However, many women who are classified as HER2-positive do not respond. Many studies have focused on the role of somatic mutations rather than germline polymorphisms in trastuzumab resistance. RESULTS: We completed an Agena MassArray screen of 10 ERBB-family single nucleotide polymorphisms (SNPs) in 194 adjuvant trastuzumab treated HER2-positive BC patients...
October 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27776045/microrna-148a-suppresses-the-proliferation-and-migration-of-pancreatic-cancer-cells-by-down-regulating-erbb3
#13
Hui Feng, Yalei Wang, Jiaojiao Su, Hongwei Liang, Chen-Yu Zhang, Xi Chen, Weiyan Yao
OBJECTIVES: ErbB3 (HER3) has been associated with pancreatic cancer progression, but little is known about its regulatory mechanisms. We investigated whether microRNAs (miRNAs) regulate levels of ErbB3 in pancreatic cancer cells. METHODS: We used bioinformatic analyses to search for miRNAs that can potentially target ERBB3. Furthermore, the biological consequences of the targeting of ERBB3 by miR-148a were examined by cell proliferation and migration assays in vitro...
October 2016: Pancreas
https://www.readbyqxmd.com/read/27768588/heregulin-expressing-her2-positive-breast-and-gastric-cancer-exhibited-heterogeneous-susceptibility-to-the-anti-her2-agents-lapatinib-trastuzumab-and-t-dm1
#14
Yoshikane Nonagase, Kimio Yonesaka, Hisato Kawakami, Satomi Watanabe, Koji Haratani, Takayuki Takahama, Naoki Takegawa, Hiroto Ueda, Junko Tanizaki, Hidetoshi Hayashi, Takeshi Yoshida, Masayuki Takeda, Yasutaka Chiba, Takao Tamura, Kazuhiko Nakagawa, Junji Tsurutani
BACKGROUND: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. RESULTS: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel...
October 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27744717/the-prospect-of-patritumab-for-treating-non-small-cell-lung-cancer
#15
Hidehito Horinouchi
The mutation or expression of HER family members serves as a therapeutic target for tyrosine kinase inhibitors or monoclonal antibodies in diverse cancers, such as non-small cell lung cancer, breast cancer, gastric cancer, head and neck cancer, colorectal cancer, pancreatic cancer and glioblastoma. HER3, which heterodimerizes with HER1 and HER2, has received much attention as a potential target for anti-EGFR treatment. Patritumab is a novel, fully human monoclonal antibody directed against HER3. Areas covered: In this review article, an overview of the market, chemistry, pharmacodynamics, pharmacokinetics, efficacy, and safety of patritumab is provided based on data from phase I studies, a combination phase I trial, and a randomized phase II trial comparing two doses of patritumab...
December 2016: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/27680564/erratum-to-heregulin-1%C3%A3-and-her3-in-hepatocellular-carcinoma-status-and-regulation-by-insulin
#16
Corina Buta, Eva Benabou, Marie Lequoy, Hélène Régnault, Dominique Wendum, Fatiha Merabtene, Hamza Chettouh, Lynda Aoudjehane, Filomena Conti, Yves Chrétien, Olivier Scatton, Olivier Rosmorduc, Françoise Praz, Laetitia Fartoux, Christèle Desbois-Mouthon
No abstract text is available yet for this article.
September 28, 2016: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/27663569/loss-of-anti-her-3-cd4-t-helper-type-1-immunity-occurs-in-breast-tumorigenesis-and-is-negatively-associated-with-outcomes
#17
Megan Fracol, Jashodeep Datta, Lea Lowenfeld, Shuwen Xu, Paul J Zhang, Carla S Fisher, Brian J Czerniecki
BACKGROUND: We previously demonstrated a progressive loss of the anti-human epidermal growth factor receptor 2 (HER2) CD4+ T-helper type 1 (Th1) response during HER2(pos) breast tumorigenesis. This loss is associated with residual disease following neoadjuvant therapy and increased risk of recurrence. In this study, we assessed the fate of anti-HER3 Th1 immunity during breast tumorigenesis. METHODS: Peripheral blood from 131 subjects, including healthy donors (HDs), patients with benign breast disease (BD), ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC), was collected...
September 23, 2016: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/27645148/primary-breast-cancer-cell-culture-yields-intra-tumor-heterogeneous-subpopulations-expressing-exclusive-patterns-of-receptor-tyrosine-kinases
#18
José Esparza-López, Pier A Ramos-Elías, Andrea Castro-Sánchez, Leticia Rocha-Zavaleta, Elizabeth Escobar-Arriaga, Alejandro Zentella-Dehesa, Eucario León-Rodríguez, Heriberto Medina-Franco, María de Jesus Ibarra-Sánchez
BACKGROUND: It has become evident that intra-tumor heterogeneity of breast cancer impact on several biological processes such as proliferation, migration, cell death and also might contribute to chemotherapy resistance. The expression of Receptor Tyrosine Kinases (RTKs) has not been analyzed in the context of intra-tumor heterogeneity in a primary breast cancer cell culture. Several subpopulations were isolated from the MBCDF (M serial-breast cancer ductal F line) primary breast cancer cells and were successfully maintained in culture and divided in two groups according to their morphology and RTKs expression pattern, and correlated with biological processes like proliferation, migration, anchorage-independent cell growth, and resistance to cytotoxic chemotherapy drugs and tyrosine kinase inhibitors (TKIs)...
2016: BMC Cancer
https://www.readbyqxmd.com/read/27618787/her2-her3-dimer-quantification-by-flim-fret-predicts-breast-cancer-metastatic-relapse-independently-of-her2-ihc-status
#19
Gregory Weitsman, Paul R Barber, Lan K Nguyen, Katherine Lawler, Gargi Patel, Natalie Woodman, Muireann T Kelleher, Sarah E Pinder, Mark Rowley, Paul A Ellis, Anand D Purushotham, Anthonius C Coolen, Boris N Kholodenko, Borivoj Vojnovic, Cheryl Gillett, Tony Ng
Overexpression of HER2 is an important prognostic marker, and the only predictive biomarker of response to HER2-targeted therapies in invasive breast cancer. HER2-HER3 dimer has been shown to drive proliferation and tumor progression, and targeting of this dimer with pertuzumab alongside chemotherapy and trastuzumab, has shown significant clinical utility. The purpose of this study was to accurately quantify HER2-HER3 dimerisation in formalin fixed paraffin embedded (FFPE) breast cancer tissue as a novel prognostic biomarker...
July 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27611608/ampulla-of-vater-carcinoma-sequencing-analysis-identifies-tp53-status-as-a-novel-independent-prognostic-factor-and-potentially-actionable-erbb-pi3k-and-wnt-pathways-gene-mutations
#20
Andrea Mafficini, Eliana Amato, Ivana Cataldo, Borislav C Rusev, Luca Bertoncello, Vincenzo Corbo, Michele Simbolo, Claudio Luchini, Matteo Fassan, Cinzia Cantù, Roberto Salvia, Giovanni Marchegiani, Giampaolo Tortora, Rita T Lawlor, Claudio Bassi, Aldo Scarpa
OBJECTIVE: To identify molecular prognostic factors and potentially actionable mutations in ampulla of Vater cancer (AVC). BACKGROUND: The largely variable outcomes of AVCs make clinical decisions difficult regarding the need of postsurgical therapy, which is based on morphological and immunohistochemical classification that do not adequately consider the varying degrees of heterogeneity present in many AVCs. No approved targeted therapies for AVC exist, but some show promising results requiring better molecular characterization to identify potential responders...
September 8, 2016: Annals of Surgery
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