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https://www.readbyqxmd.com/read/29212784/an-oligoclonal-antibody-durably-overcomes-resistance-of-lung-cancer-to-third-generation-egfr-inhibitors
#1
Maicol Mancini, Hilah Gal, Nadège Gaborit, Luigi Mazzeo, Donatella Romaniello, Tomer Meir Salame, Moshit Lindzen, Georg Mahlknecht, Yehoshua Enuka, Dominick Ga Burton, Lee Roth, Ashish Noronha, Ilaria Marrocco, Dan Adreka, Raya Eilam Altstadter, Emilie Bousquet, Julian Downward, Antonio Maraver, Valery Krizhanovsky, Yosef Yarden
Epidermal growth factor receptor (EGFR) mutations identify patients with lung cancer who derive benefit from kinase inhibitors. However, most patients eventually develop resistance, primarily due to the T790M second-site mutation. Irreversible inhibitors (e.g., osimertinib/AZD9291) inhibit T790M-EGFR, but several mechanisms, including a third-site mutation, C797S, confer renewed resistance. We previously reported that a triple mixture of monoclonal antibodies, 3×mAbs, simultaneously targeting EGFR, HER2, and HER3, inhibits T790M-expressing tumors...
December 6, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29209558/development-and-clinical-application-of-anti-her2-monoclonal-and-bispecific-antibodies-for-cancer-treatment
#2
REVIEW
Shengnan Yu, Qian Liu, Xinwei Han, Shuang Qin, Weiheng Zhao, Anping Li, Kongming Wu
HER2-targeted immunotherapy consists of monoclonal antibodies (e.g. trastuzumab, pertuzumab), bispecific antibodies (e.g. MM-111, ertumaxomab) and activated T cells armed with anti-HER2 bispecific antibody (HER2Bi-aATC). Trastuzumab is a classic drug for the treatment of HER2 positive metastatic breast cancer. The combined application of pertuzumab, trastuzumab and paclitaxel has been suggested as a standard therapy for HER2 positive advanced breast cancer. The resistance to anti-HER2 antibody has resulted in disease progression...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/29205961/her2-her3-positive-metastatic-salivary-duct-carcinoma-in-the-pleural-effusion-a-case-report
#3
Kazuya Murata, Akihiko Kawahara, Takeharu Ono, Yorihiko Takase, Hideyuki Abe, Yoshiki Naito, Jun Akiba
Salivary duct carcinoma (SDC) is an aggressive form of salivary gland tumor, and SDC patients tend to be older men, more commonly in advanced stage with a poorer prognosis. Although the cytological characteristics of SDC on fine-needle aspiration cytology have been well-described at the primary site, they have not been explored in metastasis. Here we reported a case of HER2/HER3-positive metastatic SDC in the lung and pleural effusion. The patient was a man in his 50s who had undergone extended total parotidectomy in 2008...
December 4, 2017: Diagnostic Cytopathology
https://www.readbyqxmd.com/read/29190914/genomic-copy-number-gains-of-erbb-family-members-predict-poor-clinical-outcomes-in-glioma-patients
#4
Rui Liu, Yiping Qu, Lihong Chen, Jun Pu, Sharui Ma, Xiaozhi Zhang, Qi Yang, Bingyin Shi, Peng Hou, Meiju Ji
The aim of this study was to investigate copy number of ErbB family members (including EGFR, HER2, HER3 and HER4) in a cohort of gliomas and benign meningiomas (control subjects), and explore the associations of their copy number with clinicopathological characteristics and clinical outcomes of glioma patients. Using real-time quantitative PCR assay, we demonstrated that copy number of EGFR, HER2, HER3 and HER4 in glioma patients was significantly increased compared to control subjects. Moreover, our data also showed that the risk of cancer-related death was positively associated with copy number gain (CNG) of EGFR, HER3 and HER4, but not HER2...
November 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29181099/breast-cancers-with-egfr-and-her2-co-amplification-favor-distant-metastasis-and-poor-clinical-outcome
#5
Peng Guo, Tianjie Pu, Shinan Chen, Yan Qiu, Xiaorong Zhong, Hong Zheng, Lina Chen, Hong Bu, Feng Ye
ErbB signaling serves essential roles in invasive ductal carcinoma (IDC). The aim of the present study was to assess gene amplification in ErbB family members in IDC with clinical implications. Quantitative polymerase chain reaction and fluorescence in situ hybridization were performed on formalin-fixed paraffin-embedded tumor samples for gene amplification detection. The clinical and histopathological characteristics, as well as the prognostic significance, were analyzed. Among the 119 IDC patients evaluated, epidermal growth factor receptor [EGFR; also known as human epidermal growth factor receptor (HER)1], HER2, HER3 and HER4 gene amplification was observed in 30 (25...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29180568/maternal-nanog-is-critical-for-the-zebrafish-embryo-architecture-and-for-cell-viability-during-gastrulation
#6
Marina Veil, Melanie Anna Schaechtle, Meijiang Gao, Viola Kirner, Lenka Buryanova, Rachel Grethen, Daria Onichtchouk
Nanog has been implicated in establishment of pluripotency in mammals and in zygotic genome activation in zebrafish. In this study we characterize the development of maternal and zygotic MZnanog null mutant zebrafish embryos. Without functional Nanog, epiboly is severely affected, embryo axes do not form and massive cell death starts at the end of gastrulation. We show that three independent defects in MZnanog mutants contribute to epiboly failure: yolk microtubule organization required for epiboly is abnormal, maternal mRNA fails to degrade due to the absence of miR-430 and actin structure of the yolk syncytial layer does not form properly...
November 27, 2017: Development
https://www.readbyqxmd.com/read/29179520/a-comprehensive-review-of-heregulins-her3-and-her4-as-potential-therapeutic-targets-in-cancer
#7
REVIEW
Jose Mauricio Mota, Katharine Ann Collier, Ricardo Lima Barros Costa, Timothy Taxter, Aparna Kalyan, Caio A Leite, Young Kwang Chae, Francis J Giles, Benedito A Carneiro
Heregulins (HRGs) bind to the receptors HER3 or HER4, induce receptor dimerization, and trigger downstream signaling that leads to tumor progression and resistance to targeted therapies. Increased expression of HRGs has been associated with worse clinical prognosis; therefore, attempts to block HRG-dependent tumor growth have been pursued. This manuscript summarizes the function and signaling of HRGs and review the preclinical evidence of its involvement in carcinogenesis, prognosis, and treatment resistance in several malignancies such as colorectal cancer, non-small cell lung cancer, ovarian cancer, and breast cancer...
October 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/29138285/expression-and-prognostic-significance-of-human-epidermal-growth-factor-receptors-1-2-and-3-in-oesophageal-and-gastric-adenocarcinomas-preneoadjuvant-and-postneoadjuvant-treatment
#8
Charlotta Hedner, David Borg, Björn Nodin, Emelie Karnevi, Karin Jirström, Jakob Eberhard
AIMS: Neoadjuvant treatment has now become the standard of care for oesophageal and gastric cancer. The aim of this study was to investigate the influence of neoadjuvant therapy on the expression of human epidermal growth factor receptor 1 (HER1/EGFR), HER2 and HER3, in oesophageal and gastric adenocarcinoma. METHODS: Immunohistochemical expression of EGFR, HER2 and HER3 was examined and compared in pretreatment biopsies, post-treatment surgical resection specimens and metastases in a retrospective cohort of 166 patients with adenocarcinoma of the oesophagus or stomach...
November 14, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29127433/targeting-and-suppression-of-her3-positive-breast-cancer-by-t-lymphocytes-expressing-a-heregulin-chimeric-antigen-receptor
#9
Bai-Le Zuo, Bo Yan, Guo-Xu Zheng, Wen-Jin Xi, Xiao Zhang, An-Gang Yang, Lin-Tao Jia
Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors...
November 10, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29109513/targeting-androgen-receptor-in-treating-her2-positive-breast-cancer
#10
Licai He, Zhuanyun Du, Xusheng Xiong, Hua Ma, Zhenfeng Zhu, Hongwei Gao, Jiawei Cao, Tong Li, Hongzhi Li, Kaiyan Yang, Guorong Chen, Jennifer K Richer, Haihua Gu
Androgen receptor (AR) is widely expressed in different subtypes of breast cancer (BC). However, it is unclear how AR functions in HER2 positive (+) BC. Knockdown of AR with shRNAs and a new generation anti-androgen drug, Enzalutamide, were used to explore the involvement of AR on the growth of HER2 + BC cells (HCC1954 and SKBR3). AR shRNA or Enzalutamide inhibited the growth of SKBR3 cells at a similar extend compared to trastuzumab, an approved HER2 targeted drug. Combining Enzalutamide with trastuzumab further decreased the growth of HCC1954 and SKBR3 cells compared with single agent alone in vitro...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29080749/flubendazole-overcomes-trastuzumab-resistance-by-targeting-cancer-stem-like-properties-and-her2-signaling-in-her2-positive-breast-cancer
#11
Yoon-Jae Kim, Daeil Sung, Eunhye Oh, Youngkwan Cho, Tae-Min Cho, Lee Farrand, Jae Hong Seo, Ji Young Kim
Although trastuzumab provides significant clinical benefit for HER2-positive breast cancers, responses are limited by the emergence of resistance. Trastuzumab resistance is a multi-factorial phenomenon thought to arise from the presence of cancer stem cells and interactions between truncated p95HER2 and HER family members. Flubendazole (FLU) is a potent anthelmintic agent with an exceptional safety profile. Evidence also suggests that it can act as an anticancer agent in several cancer cell types. We sought to investigate the effect of FLU on apoptosis, HER2/Akt signaling, breast cancer stem cell (BCSC)-like properties and trastuzumab resistance in HER2-positive breast cancer cells...
November 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29080385/evaluation-of-patritumab-with-or-without-erlotinib-in-combination-with-standard-cytotoxic-agents-against-pediatric-sarcoma-xenograft-models
#12
Abhik Bandyopadhyay, Edward Favours, Doris A Phelps, Vanessa Del Pozo, Samson Ghilu, Dias Kurmashev, Joel Michalek, Aron Trevino, Denis Guttridge, Cheryl London, Kenji Hirotani, Ling Zhang, Raushan T Kurmasheva, Peter J Houghton
BACKGROUND: Integrating molecularly targeted agents with cytotoxic drugs used in curative treatment of pediatric cancers is complex. An evaluation was undertaken with the ERBB3/Her3-specific antibody patritumab (P) either alone or with the ERBB1/epidermal growth factor receptor inhibitor erlotinib (E) in combination with standard cytotoxic agents, cisplatin, vincristine, and cyclophosphamide, in pediatric sarcoma xenograft models that express receptors and ligands targeted by these agents...
October 28, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29075780/association-of-tumor-her3-messenger-rna-expression-with-panitumumab-efficacy-in-advanced-colorectal-cancer
#13
Jenny F Seligmann, Ace J Hatch, Susan D Richman, Faye Elliott, Bart Jacobs, Sarah Brown, Herbert Hurwitz, Jennifer H Barrett, Philip Quirke, Andrew B Nixon, Matthew T Seymour
Importance: Epidermal growth factor receptor (EGFR) (HER1) signaling depends on ligand binding and dimerization with itself or other HER receptors. We previously showed in a randomized trial that high EGFR ligand expression is predictive of panitumumab benefit in advanced colorectal cancer. Tumor expression of HER3 may further refine the RAS wild-type (wt) population benefitting from anti-EGFR agents. Objective: To examine HER3 messenger RNA expression as a prognostic and predictive biomarker for anti-EGFR therapy in a randomized clinical trial of panitumumab...
October 26, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/29059433/an-erbb1-3-neutralizing-antibody-mixture-with-high-activity-against-drug-resistant-her2-breast-cancers-with-erbb-ligand-overexpression
#14
Luis J Schwarz, Katherine E Hutchinson, Brent N Rexer, Mónica Valeria Estrada, Paula I Gonzalez Ericsson, Melinda E Sanders, Teresa C Dugger, Luigi Formisano, Angel Guerrero-Zotano, Monica Red-Brewer, Christian D Young, Johan Lantto, Mikkel W Pedersen, Michael Kragh, Ivan D Horak, Carlos L Arteaga
Background: Plasticity of the ERBB receptor network has been suggested to cause acquired resistance to anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we studied whether a novel approach using an ERBB1-3-neutralizing antibody mixture can block these compensatory mechanisms of resistance. Methods: HER2+ cell lines and xenografts (n ≥ 6 mice per group) were treated with the ERBB1-3 antibody mixture Pan-HER, trastuzumab/lapatinib (TL), trastuzumab/pertuzumab (TP), or T-DM1...
November 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29048656/nrg1-dependent-activation-of-her3-induces-primary-resistance-to-trastuzumab-in-her2-overexpressing-breast-cancer-cells
#15
Liuting Yang, Yingying Li, Enyun Shen, Fengqi Cao, Li Li, Xiaojin Li, Xuejiang Wang, Seyed Kariminia, Bingmei Chang, Hongzhong Li, Qin Li
This study was conducted to determine the role of neuregulin 1 (NRG1)-dependent human epidermal growth factor receptor 3 (HER3) activation in trastuzumab primary resistance, and to observe the inhibitory effect of HER3 monoclonal antibody on HER2-overexpressing breast cancer cells. BT474 cells (trastuzumab sensitive) and MDA-MB-453 cells (trastuzumab resistant) were first stimulated with NRG1 and then treated with either trastuzumab, HER3 antibody, or a combination of both. The expression of phospho human epidermal growth factor receptor 2 (p-HER2), phospho human epidermal growth factor receptor 3 (p-HER3), phospho protein kinase B (p-Akt) and phospho mitogen-activated protein kinase (p-MAPK) were detected by western blotting...
November 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29039474/evaluation-of-a-radiocobalt-labelled-affibody-molecule-for-imaging-of-human-epidermal-growth-factor-receptor-3-expression
#16
Maria Rosestedt, Ken G Andersson, Bogdan Mitran, Sara S Rinne, Vladimir Tolmachev, John Löfblom, Anna Orlova, Stefan Ståhl
The human epidermal growth factor receptor 3 (HER3) is involved in the development of cancer resistance towards tyrosine kinase-targeted therapies. Several HER3‑targeting therapeutics are currently under clinical evaluation. Non-invasive imaging of HER3 expression could improve patient management. Affibody molecules are small engineered scaffold proteins demonstrating superior properties as targeting probes for molecular imaging compared with monoclonal antibodies. Feasibility of in vivo HER3 imaging using affibody molecules has been previously demonstrated...
October 11, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29024937/protein-biomarkers-predictive-for-response-to-anti-egfr-treatment-in-ras-wild-type-metastatic-colorectal-carcinoma
#17
Astrid Lièvre, Bérèngere Ouine, Jim Canet, Aurélie Cartier, Yael Amar, Wulfran Cacheux, Odette Mariani, Rosine Guimbaud, Janick Selves, Thierry Lecomte, Serge Guyetant, Ivan Bieche, Frédérique Berger, Leanne de Koning
BACKGROUND: Metastatic colorectal cancer (mCRC) patients with mutant KRAS or NRAS are ineligible for anti-epidermal growth factor receptor (anti-EGFR) therapy, as RAS mutations activate downstream pathways independently of EGFR and induce primary resistance. However, even among RAS wild-type (WT) patients, only a fraction responds to anti-EGFR therapy, suggesting that other mechanisms of resistance exist. We hypothesise that different (epi)genetic alterations can lead to primary anti-EGFR resistance and that the crucial end point is the activation of protein signalling pathways...
October 12, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28979811/a-novel-multi-target-inhibitor-harboring-selectivity-of-inhibiting-egfr-t790m-sparing-wild-type-egfr
#18
Xiaoping Song, Xin Qi, Qiang Wang, Weiming Zhu, Jing Li
Non-Small Cell Lung Cancer (NSCLC) is driven by a variety of deregulated kinases and the development of multi-target inhibitor for multiple signaling pathways or multiple steps is required. Here, we reported that ZWM026, an indolocarbazoles analogue, derived from mangrove in coastal marine wetland, exhibited selectivity and reversibility against T790M mutant over wild-type EGFR in naturally occurring NSCLC cells and constructed NIH-3T3 cells. It simultaneously inhibited activities of HER2, HER3, HER4 and RET but was different from current multi-target kinase inhibitors...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28978022/prognostic-significance-of-her3-in-patients-with-malignant-solid-tumors
#19
Qin Li, RuiXue Zhang, Han Yan, PengFei Zhao, Li Wu, Hui Wang, Teng Li, Bangwei Cao
Human epidermal growth factor receptor 3 (HER3) is closely involved in tumor progression and is an important target of therapy. To evaluate the prognostic significance of HER3 in malignant solid tumors, we searched the PUBMED, EMBASE and CNKI databases for relevant studies written in English or Chinese up to December 2015. Fifteen studies comprising 2964 patients were identified. The HER3(+) rate ranged from 9.0-75.1 % in malignant solid tumors: 30.3-75.1 % in breast cancers, 51.1-74.5 % in colorectal cancers, 13...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28963699/nrg-1-stimulates-serum-dj-1-increase-in-breast-cancers
#20
Yuandong Wang, Yan Zhang, Qian Lu, Yiming Wang, Xinchen Sun, Shu Zhang
To explore the relationship between the expression of DJ-1/HER3 and tumor grade in breast cancer, and investigate the effect of HER3 on NRG-1-mediated serum DJ-1 level in vivo. We analyze the expression level of DJ-1 and HER3 in 68 patients with different grades of breast cancer by immunostaining the tissue microarray. Besides, we investigated the serum DJ-1 level by ELISA. We found that the detectable DJ-1 protein expression is decreased, and the HER3 expression is increased in tumor tissue with the progression of breast cancer...
September 30, 2017: Pathology Oncology Research: POR
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