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https://www.readbyqxmd.com/read/28320942/egf-and-nrg-induce-phosphorylation-of-her3-erbb3-by-egfr-using-distinct-oligomeric-mechanisms
#1
Bettina van Lengerich, Christopher Agnew, Elias M Puchner, Bo Huang, Natalia Jura
Heteromeric interactions between the catalytically impaired human epidermal growth factor receptor (HER3/ERBB3) and its catalytically active homologs EGFR and HER2 are essential for their signaling. Different ligands can activate these receptor pairs but lead to divergent signaling outcomes through mechanisms that remain largely unknown. We used stochastic optical reconstruction microscopy (STORM) with pair-correlation analysis to show that EGF and neuregulin (NRG) can induce different extents of HER3 clustering that are dependent on the nature of the coexpressed HER receptor...
March 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28302091/development-of-a-test-that-measures-real-time-her2-signaling-function-in-live-breast-cancer-cell-lines-and-primary-cells
#2
Yao Huang, David J Burns, Benjamin E Rich, Ian A MacNeil, Abhijit Dandapat, Sajjad M Soltani, Samantha Myhre, Brian F Sullivan, Carol A Lange, Leo T Furcht, Lance G Laing
BACKGROUND: Approximately 18-20% of all human breast cancers have overexpressed human epidermal growth factor receptor 2 (HER2). Standard clinical practice is to treat only overexpressed HER2 (HER2+) cancers with targeted anti-HER2 therapies. However, recent analyses of clinical trial data have found evidence that HER2-targeted therapies may benefit a sub-group of breast cancer patients with non-overexpressed HER2. This suggests that measurement of other biological factors associated with HER2 cancer, such as HER2 signaling pathway activity, should be considered as an alternative means of identifying patients eligible for HER2 therapies...
March 16, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28286209/esophageal-adenocarcinoma-cells-and-xenograft-tumors-exposed-to-erb-b2-receptor-tyrosine-kinase-2-and-3-inhibitors-activate-transforming-growth-factor-beta-signaling-which-induces-epithelial-to-mesenchymal-transition
#3
Eva A Ebbing, Anne Steins, Evelyn Fessler, Phylicia Stathi, Willem Joost Lesterhuis, Kausilia K Krishnadath, Louis Vermeulen, Jan Paul Medema, Maarten F Bijlsma, Hanneke W M van Laarhoven
BACKGROUND & AIMS: Drugs that inhibit the erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) are the standard treatment of patients with different types of cancer, including HER2-overexpressing gastroesophageal tumors. Unfortunately, cancer cells become resistant to these drugs, so overall these drugs provide little benefit to patients with these tumors. We investigated mechanisms that mediate resistance of esophageal adenocarcinoma (EAC) cells and patient-derived xenograft (PDX) tumors to ERBB inhibitors...
March 9, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28280605/next-generation-sequencing-identifies-interactome-signatures-in-relapsed-and-refractory-metastatic-colorectal-cancer
#4
Benny Johnson, Laurence Cooke, Daruka Mahadevan
BACKGROUND: In the management of metastatic colorectal cancer (mCRC), KRAS, NRAS and BRAF mutational status individualizes therapeutic options and identify a cohort of patients (pts) with an aggressive clinical course. We hypothesized that relapsed and refractory mCRC pts develop unique mutational signatures that may guide therapy, predict for a response and highlight key signaling pathways important for clinical decision making. METHODS: Relapsed and refractory mCRC pts (N=32) were molecularly profiled utilizing commercially available next generation sequencing (NGS) platforms...
February 2017: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28248115/engineered-multivalency-enhances-affibody-based-her3-inhibition-and-downregulation-in-cancer-cells
#5
John S Schardt, Jinan M Oubaid, Sonya C Williams, James L Howard, Chloe M Aloimonos, Michelle L Bookstaver, Tek N Lamichhane, Sonja Sokic, Mariya S Liyasova, Maura O'Neill, Thorkell Andresson, Arif Hussain, Stanley Lipkowitz, Steven M Jay
The receptor tyrosine kinase HER3 has emerged as a therapeutic target in ovarian, prostate, breast, lung, and other cancers due to its ability to potently activate the PI3K/Akt pathway, especially via dimerization with HER2, as well as for its role in mediating drug resistance. Enhanced efficacy of HER3-targeted therapeutics would therefore benefit a wide range of patients. This study evaluated the potential of multivalent presentation, through protein engineering, to enhance the effectiveness of HER3-targeted affibodies as alternatives to monoclonal antibody therapeutics...
March 8, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28238967/resveratrol-fuels-her2-and-er%C3%AE-positive-breast-cancer-behaving-as-proteasome-inhibitor
#6
Cristina Andreani, Caterina Bartolacci, Kathleen Wijnant, Rita Crinelli, Marzia Bianchi, Mauro Magnani, Albana Hysi, Manuela Iezzi, Augusto Amici, Cristina Marchini
The phytoestrogen resveratrol has been reported to possess cancer chemo-preventive activity on the basis of its effects on tumor cell lines and xenograft or carcinogen-inducible in vivo models. Here we investigated the effects of resveratrol on spontaneous mammary carcinogenesis using Δ16HER2 mice as HER2+/ERα+ breast cancer model. Instead of inhibiting tumor growth, resveratrol treatment (0.0001% in drinking water; daily intake of 4μg/mouse) shortened tumor latency and enhanced tumor multiplicity in Δ16HER2 mice...
February 26, 2017: Aging
https://www.readbyqxmd.com/read/28236978/circulating-heregulin-level-is-associated-with-the-efficacy-of-patritumab-combined-with-erlotinib-in-patients-with-non-small-cell-lung-cancer
#7
Kimio Yonesaka, Kenji Hirotani, Joachim von Pawel, Mircea Dediu, Shuquan Chen, Catherine Copigneaux, Kazuhiko Nakagawa
OBJECTIVES: Patritumab is a fully human anti-human epidermal growth factor receptor 3 (HER3) antibody that blocks activation by its ligand, heregulin (HRG). Preclinical studies have demonstrated the efficacy of patritumab in aberrantly high HRG-expressing non-small cell lung cancer (NSCLC). In the phase II randomized, placebo-controlled double-blind study HERALD (n=212 patients with NSCLC), patritumab plus erlotinib did not improve progression-free survival (PFS) compared with placebo plus erlotinib...
March 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28235665/an-in-silico-approach-to-find-a-peptidomimetic-targeting-extracellular-domain-of-her3-from-a-her3-nanobody
#8
Z Pourhashem, M Mehrpouya, N Yardehnavi, A Eslamparast, F Kazemi-Lomedasht
HER3 is an important therapeutic target in cancer treatments. HER3 Nanobodies (Nbs) are a novel class of antibodies with several competitive advantages over conventional antibodies. A peptidomimetic derived from these Nbs can be considered to be a small peptide mimicking some of the molecular recognition interactions of a natural peptide or protein in a three-dimensional (3D) space, with a receptor that has improved properties. In this study, we introduce a new approach to design a peptidomimetic derived from HER3 Nb through an in silico analysis...
February 10, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28230065/in-vivo-evaluation-of-a-novel-format-of-a-bivalent-her3-targeting-and-albumin-binding-therapeutic-affibody-construct
#9
Tarek Z Bass, Maria Rosestedt, Bogdan Mitran, Fredrik Y Frejd, John Löfblom, Vladimir Tolmachev, Stefan Ståhl, Anna Orlova
Overexpression of human epidermal growth factor receptor 3 (HER3) is involved in resistance to several therapies for malignant tumours. Currently, several anti-HER3 monoclonal antibodies are under clinical development. We introduce an alternative approach to HER3-targeted therapy based on engineered scaffold proteins, i.e. affibody molecules. We designed a small construct (22.5 kDa, denoted 3A3), consisting of two high-affinity anti-HER3 affibody molecules flanking an albumin-binding domain ABD, which was introduced for prolonged residence in circulation...
February 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28218686/natural-products-as-chemopreventive-agents-by-potential-inhibition-of-the-kinase-domain-in-erbb-receptors
#10
Maria Olivero-Acosta, Wilson Maldonado-Rojas, Jesus Olivero-Verbel
Small molecules found in natural products provide therapeutic benefits due to their pharmacological or biological activity, which may increase or decrease the expression of human epidermal growth factor receptor (HER), a promising target in the modification of signaling cascades involved in excessive cellular growth. In this study, in silico molecular protein-ligand docking protocols were performed with AutoDock Vina in order to evaluate the interaction of 800 natural compounds (NPs) from the NatProd Collection (http://www...
February 17, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28144730/phase-1-study-of-new-formulation-of-patritumab-u3-1287-process-2-a-fully-human-anti-her3-monoclonal-antibody-in-combination-with-erlotinib-in-japanese-patients-with-advanced-non-small-cell-lung-cancer
#11
Toshio Shimizu, Kimio Yonesaka, Hidetoshi Hayashi, Tsutomu Iwasa, Koji Haratani, Hironori Yamada, Shoichi Ohwada, Emi Kamiyama, Kazuhiko Nakagawa
BACKGROUND: This phase 1 study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287) Process 2, a new formulation of fully human anti-HER3 monoclonal antibody in combination with erlotinib, an epidermal growth factor receptortyrosine kinase inhibitor (EGFR-TKI) in prior chemotherapy treated Japanese patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients received intravenous patritumab Process 2 formulation at 9 mg/kg every 3 weeks after initiation of 18 mg/kg loading dose combined with continuous daily dose of erlotinib (150 mg QD) until any of the withdrawal criteria are met...
March 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28139652/lnc-ing-ror1-her3-and-hippo-signalling-in-metastasis
#12
Wei Zhuo, Yibin Kang
Long noncoding RNAs (lncRNAs) are increasingly recognized for their role in cancer progression. The previously uncharacterized lncRNA MAYA is now shown to promote bone metastasis by bridging ROR1-HER3 and Hippo-YAP pathways. Neuregulin-induced HER3 phosphorylation by ROR1 recruits a MAYA-containing protein complex to methylate Hippo/MST1 and activate YAP target genes that are essential for bone metastasis.
January 31, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28123607/proteins-involved-in-her2-signalling-pathway-their-relations-and-influence-on-metastasis-free-survival-in-her2-positive-breast-cancer-patients-treated-with-trastuzumab-in-adjuvant-setting
#13
Agnieszka Adamczyk, Aleksandra Grela-Wojewoda, Małgorzata Domagała-Haduch, Aleksandra Ambicka, Agnieszka Harazin-Lechowska, Anna Janecka, Ida Cedrych, Kaja Majchrzyk, Anna Kruczak, Janusz Ryś, Joanna Niemiec
AIM: Resistance to trastuzumab (which is a standard therapy for breast cancer patients with HER2 overexpression) is associated with higher risk of progression or cancer death, and might be related to activation of signalling cascades (PI3K/AKT/mTOR, Ras/Raf/MAPK) and decreased level of their inhibitors. MATERIAL AND METHODS: Formalin-fixed paraffin-embedded tumour specimens from 118 HER2-overexpressing breast cancer patients treated with radical local therapy and trastuzumab in adjuvant setting were used for the assessment of: (1) PIK3CA gene mutations (p...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28114269/a-ror1-her3-lncrna-signalling-axis-modulates-the-hippo-yap-pathway-to-regulate-bone-metastasis
#14
Chunlai Li, Shouyu Wang, Zhen Xing, Aifu Lin, Ke Liang, Jian Song, Qingsong Hu, Jun Yao, Zhongyuan Chen, Peter K Park, David H Hawke, Jianwei Zhou, Yan Zhou, Shuxing Zhang, Han Liang, Mien-Chie Hung, Gary E Gallick, Leng Han, Chunru Lin, Liuqing Yang
Bone metastases remain a serious health concern because of limited therapeutic options. Here, we report that crosstalk between ROR1-HER3 and the Hippo-YAP pathway promotes breast cancer bone metastasis in a long noncoding RNA-dependent fashion. Mechanistically, the orphan receptor tyrosine kinase ROR1 phosphorylates HER3 at a previously unidentified site Tyr1307, following neuregulin stimulation, independently of other ErbB family members. p-HER3 Tyr1307 recruits the LLGL2-MAYA-NSUN6 RNA-protein complex to methylate Hippo/MST1 at Lys59...
February 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28105244/her2-overexpression-reverses-the-relative-resistance-of-egfr-mutant-h1975-cell-line-to-gefitinib
#15
Jing Xu, Li Shen, Bi-Cheng Zhang, Wen-Hong Xu, Shu-Qin Ruan, Chi Pan, Qi-Chun Wei
Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that has been demonstrated to be clinically useful for the treatment of patients with non-small cell lung cancer (NSCLC). However, ~50% of patients do not respond to EGFR TKI treatment through the emergence of mutations, such as T790M. Therefore, it is important to determine which patients are eligible for treatment with gefitinib. As a preferred dimerization partner for EGFR, the role of EGFR 2 (HER2) in mediating sensitivity to gefitinib is poorly understood...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28087106/charge-variant-analysis-of-proposed-biosimilar-to-trastuzumab
#16
Pravinkumar Dakshinamurthy, Pavithra Mukunda, Bhargav Prasad Kodaganti, Bharath Ravindra Shenoy, Bairavabalakumar Natarajan, Amol Maliwalave, Vivek Halan, Sathyabalan Murugesan, Sunit Maity
Trastuzumab is a humanized monoclonal antibody (mAb) employed for the treatment of HER2 Positive Breast Cancer. A HER2 overexpressing tumor cell binds to Trastuzumab and attracts immune cells which lead to induction of Antibody Dependent Cellular Cytotoxicity (ADCC) by binding to Fc receptors (CD16a or FcγRIIIa) on an effector cell, such as natural killer (NK) cells. The most commonly expressed receptor on NK cell is CD16a which binds to the Fc portion of Trastuzumab. The ligand-independent HER2-HER3 dimerization is the most potent stimulator of downstream pathways for regulation of cell growth and survival...
January 10, 2017: Biologicals: Journal of the International Association of Biological Standardization
https://www.readbyqxmd.com/read/28078108/egfr-family-and-cmet-expression-profiles-and-prognostic-significance-in-esophagogastric-adenocarcinoma
#17
Ellie Chan, Ahmad Alkhasawneh, Lizette Vila Duckworth, Tabish Aijaz, Tania Zuluaga Toro, Xiaomin Lu, Steven J Hughes, Amy Collinsworth, Thomas J George
BACKGROUND: Targeted therapy with anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibody in patients with HER2 overexpressed esophagogastric adenocarcinoma (EGA) improves survival; however, the effect is transient due to the development of resistance. Some studies suggest that cMet overexpression provides cross talk for epidermal growth factor receptor (EGFR) and HER2 inhibition. We sought to characterize the expression profile of the EGFR family and cMet receptors in untreated, resected EGA...
December 2016: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28057664/incidence-and-management-of-diarrhea-in-patients-with-her2-positive-breast-cancer-treated-with-pertuzumab
#18
S M Swain, A Schneeweiss, L Gianni, J J Gao, A Stein, M Waldron-Lynch, S Heeson, M S Beattie, B Yoo, J Cortes, J Baselga
BACKGROUND: Pertuzumab disrupts heterodimerization between human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), HER3, and HER4. Thus, pertuzumab could result in adverse events similar to those observed with EGFR antagonists, such as diarrhea. We report the incidence and severity of diarrhea observed with pertuzumab in the CLEOPATRA, NeoSphere, and TRYPHAENA studies. PATIENTS AND METHODS: Patients (n=1443) had metastatic (CLEOPATRA [n=804]) or early-stage breast cancer (NeoSphere [n=416] and TRYPHAENA [n=223])...
January 5, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28049763/the-receptor-tyrosine-kinase-axl-mediates-nuclear-translocation-of-the-epidermal-growth-factor-receptor
#19
Toni M Brand, Mari Iida, Kelsey L Corrigan, Cara M Braverman, John P Coan, Bailey G Flanigan, Andrew P Stein, Ravi Salgia, Jana Rolff, Randall J Kimple, Deric L Wheeler
The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance...
January 3, 2017: Science Signaling
https://www.readbyqxmd.com/read/28036286/her3-and-linc00052-interplay-promotes-tumor-growth-in-breast-cancer
#20
Ahmad Salameh, Xuejun Fan, Byung-Kwon Choi, Shu Zhang, Ningyan Zhang, Zhiqiang An
Here we report that the lncRNA LINC00052 expression correlates positively with HER3/ErbB3 levels in breast cancer cells. Gene silencing of LINC00052 diminished both LINC00052 and HER3 expression and reduced cancer cell growth in vitro and in vivo. LINC00052 overexpression promoted cancer cell growth in vitro and in vivo and increased HER3-mediated downstream signaling. Importantly, neutralization of HER3 signaling with HER3 targeting monoclonal antibodies blocked LINC00052 mediated cancer cell proliferation in vitro and tumor growth in vivo, suggesting LINC00052 promoting cancer growth through HER3 signaling...
January 24, 2017: Oncotarget
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