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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
#1
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...
January 31, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28139652/lnc-ing-ror1-her3-and-hippo-signalling-in-metastasis
#2
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
#3
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
#4
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...
January 23, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28105244/her2-overexpression-reverses-the-relative-resistance-of-egfr-mutant-h1975-cell-line-to-gefitinib
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/28032592/feedback-activation-of-her3-attenuates-response-to-egfr-inhibitors-in-colon-cancer-cells
#11
Albert Bosch-Vilaró, Bart Jacobs, Valentina Pomella, Layka Abbasi Asbagh, Richard Kirkland, Joe Michel, Sharat Singh, Xinjun Liu, Phillip Kim, Gregory Weitsman, Paul R Barber, Borivoj Vojnovic, Tony Ng, Sabine Tejpar
The EGFR inhibitor cetuximab is approved for the treatment of colorectal cancer. However, both innate and acquired resistance mechanisms, including compensatory feedback loops, limit its efficacy. Nevertheless, the emergence of these feedback loops has remained largely unexplored to date. Here, we showed feedback upregulation of HER3 and induction of HER3 phosphorylation after cetuximab treatment in colon cancer cells. We also showed that this upregulation occurs, at least partly, through AKT inhibition. Together with this, we observed increased HER2:HER3 dimerization upon cetuximab treatment...
December 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/28031425/phase-ib-study-of-safety-and-pharmacokinetics-of-the-pi3k-inhibitor-sar245408-with-the-her3-neutralizing-human-antibody-sar256212-in-patients-with-solid-tumors
#12
Vandana G Abramson, Jeffrey G Supko, Tarah Ballinger, James M Cleary, John F Hilton, Sara Tolaney, Nicole G Chau, Daniel C Cho, Joanne J Lager, Joseph Pearlberg, Geoffrey I Shapiro, Carlos L Arteaga
PURPOSE: This phase Ib study was designed to determine the maximum tolerated dose, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) monoclonal antibody SAR256212 in combination with the oral phosphoinositide 3-kinase (PI3K) inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors. EXPERIMENTAL DESIGN: Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3+3 dose escalation design until occurrence of disease progression or dose-limiting toxicity...
December 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28000159/her3-as-a-therapeutic-target-in-cancer
#13
REVIEW
Niki Karachaliou, Chiara Lazzari, Alberto Verlicchi, Aaron E Sosa, Rafael Rosell
Targeting members of the human epidermal growth factor receptor family, especially EGFR and HER2, has been an established strategy for the treatment of tumors with abnormally activated receptors due to overexpression, mutation, ligand-dependent receptor dimerization and ligand-independent activation. Less attention has been paid to the oncogenic activity of HER3, although there is growing evidence that it mediates resistance to EGFR and HER2 pathway directed therapies. The main caveat for the development of effective HER3 targeted therapies is the absence of a strong enzymatic activity to target, as well as the limited potential for single-agent activity...
February 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/27986750/human-papillomavirus-regulates-her3-expression-in-head-and-neck-cancer-implications-for-targeted-her3-therapy-in-hpv-patients
#14
Toni M Brand, Stefan Hartmann, Neil E Bhola, Noah D Peyser, Hua Li, Yan Zeng, Erin Isaacson Wechsler, Max V Ranall, Sourav Bandyopadhyay, Umamaheswar Duvvuri, Theresa M LaVallee, Richard C K Jordan, Daniel E Johnson, Jennifer R Grandis
PURPOSE: Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of HNSCCs, where viral expression of the E6 and E7 oncoproteins are necessary for tumor growth and maintenance. Although patients with HPV(+) tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV(+) vs. HPV(-) tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide 3-kinase (PI3K) in HPV(+) tumors...
December 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27981460/her2-her3-pathway-in-biliary-tract-malignancies-systematic-review-and-meta-analysis-a-potential-therapeutic-target
#15
Salvatore Galdy, Angela Lamarca, Mairéad G McNamara, Richard A Hubner, Chiara A Cella, Nicola Fazio, Juan W Valle
Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs...
December 15, 2016: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/27942917/ljm716-in-japanese-patients-with-head-and-neck-squamous-cell-carcinoma-or-her2-overexpressing-breast-or-gastric-cancer
#16
Shunji Takahashi, Takayuki Kobayashi, Junichi Tomomatsu, Yoshinori Ito, Hisanobu Oda, Tatsuhiro Kajitani, Tomoyuki Kakizume, Takeshi Tajima, Hiromi Takeuchi, Heiko Maacke, Taito Esaki
PURPOSE: Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients...
January 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27941874/hrg-her2-her3-signaling-promotes-ahr-mediated-memo-1-expression-and-migration-in-colorectal-cancer
#17
V Bogoevska, G Wolters-Eisfeld, B T Hofmann, A T El Gammal, B Mercanoglu, F Gebauer, Y K Vashist, D Bogoevski, D Perez, N Gagliani, J R Izbicki, M Bockhorn, C Güngör
Colorectal cancer (CRC) is a complex disease with still unsatisfactory prognosis even in western societies, although substantial progress has been made in pre-screening programs, surgical techniques and targeted therapy options. Mediator of motility-1 (Memo-1) was previously recognized as an important effector of cell migration downstream of receptor tyrosine kinase signaling in breast cancer. This study identified Memo-1 as frequently overexpressed in CRC and established a close link between extracellular HER2 activation, AhR/ARNT transcriptional activity and Memo-1 expression...
December 12, 2016: Oncogene
https://www.readbyqxmd.com/read/27930489/screening-and-preliminary-verification-of-a-phage-display-single-chain-antibody-library-against-coal-workers-pneumoconiosis
#18
Guang-Hui Zhang, Li Li, Changfu Hao, Jing-Chao Ren, Hongyi Zhang, Jie Jiao, Liyun Gao, Shibin Ding, Sanqiao Yao, Wu Yao, Weidong Wu
OBJECTIVES: To construct a phage display human antibody library (PDHAL) against pneumoconiosis for the diagnosis and treatment of coal worker pneumoconiosis (CWP). METHODS: The PDHAL was established via CWP blood and six positive antibodies were discovered. 867 coal workers (558 CWP and 309 without CWP) and 393 controls were recruited to validate the results. RESULTS: A PDHAL against CWP was established, from which six strong positive clones were selected, sequenced and identified as VEGF, interleukin-18, HSP70, HER3, Gz-B and RF...
December 2016: Journal of Occupational and Environmental Medicine
https://www.readbyqxmd.com/read/27913862/prognostic-impact-of-her3-based-on-protein-and-mrna-expression-in-high-grade-serous-ovarian-carcinoma
#19
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)...
February 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/27903463/her2-transmembrane-domain-tmd-mutations-v659-g660-that-stabilize-homo-and-heterodimerization-are-rare-oncogenic-drivers-in-lung-adenocarcinoma-that-respond-to-afatinib
#20
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: Erb-b2 receptor tyrosine kinase (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 8551 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...
November 27, 2016: Journal of Thoracic Oncology
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