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Herceptin resistance

Huiping Shi, Weili Zhang, Qiaoming Zhi, Min Jiang
In the era of new and mostly effective molecular targeted therapies, human epidermal growth factor receptor 2 positive (HER2+) cancers are still intractable diseases. Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor, has greatly improved breast cancer prognosis in recent years after the initial introduction of trastuzumab (Herceptin). However, clinical evidence indicates the existence of both primary unresponsiveness and secondary lapatinib resistance, which leads to the failure of this agent in HER2+ cancer patients...
October 10, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
T Yu, G Yang, Y Hou, X Tang, C Wu, X-A Wu, L Guo, Q Zhu, H Luo, Y-E Du, S Wen, L Xu, J Yin, G Tu, M Liu
Multiple drug resistance is a challenging issue in the clinic. There is growing evidence that the G-protein-coupled estrogen receptor (GPER) is a novel mediator in the development of multidrug resistance in both estrogen receptor (ER)-positive and -negative breast cancers, and that cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be a new agent that promotes drug resistance in tumor cells. However, the role of cytoplasmic GPER of CAFs on tumor therapy remains unclear. Here we first show that the breast tumor cell-activated PI3K/AKT (phosphoinositide 3-kinase/AKT) signaling pathway induces the cytoplasmic GPER translocation of CAFs in a CRM1-dependent pattern, and leads to the activation of a novel estrogen/GPER/cAMP/PKA/CREB signaling axis that triggers the aerobic glycolysis switch in CAFs...
October 10, 2016: Oncogene
S Lefort, A Thuleau, Y Kieffer, P Sirven, I Bieche, E Marangoni, A Vincent-Salomon, F Mechta-Grigoriou
The CXCR4 receptor and its ligand CXCL12 (also named stromal cell-derived factor 1, SDF1) have a critical role in chemotaxis and homing, key steps in cancer metastasis. Although myofibroblasts expressing CXCL12 are associated with the presence of axillary metastases in HER2 breast cancers (BC), the therapeutic interest of targeting CXCR4/CXCL12 axis in the different BC subtypes remains unclear. Here, we investigate this question by testing antitumor activity of CXCR4 inhibitors in patient-derived xenografts (PDX), which faithfully reproduce human tumor properties...
September 26, 2016: Oncogene
Zhongxing Liang, Xuehai Bian, Hyunsuk Shim
Triple negative breast tumors don't respond to Tamoxifen and Herceptin, two of the most effective medications for treating breast cancer. Additionally, triple negative breast cancer (TNBC) intrinsically resists or will eventually acquire resistance to chemotherapy. The purpose of this study is to understand better the molecular basis of TNBC as well as develop new therapeutic strategies against it. Here, we analyzed miRNA-206 expression levels in breast cancer cell lines and tissues. In addition, we investigated whether miR-206 mimics inhibited TNBC tumor invasion and angiogenesis...
August 26, 2016: Biochemical and Biophysical Research Communications
Kyohei Muguruma, Fumika Yakushiji, Ryosuke Kawamata, Daichi Akiyama, Risako Arima, Takuya Shirasaka, Yamato Kikkawa, Akihiro Taguchi, Kentaro Takayama, Takeshi Fukuhara, Tetsuro Watabe, Yuji Ito, Yoshio Hayashi
Although several approaches for making antibody-drug conjugates (ADC) have been developed, it has yet to be reported that an antibody binding peptide such as Z33 from protein A is utilized as the pivotal unit to generate the noncovalent-type ADC (NC-ADC). Herein we aim to establish a novel probe for NC-ADC by synthesizing the Z33-conjugated antitumor agent, plinabulin. Due to the different solubility of two components, including hydrophobic plinabulin and hydrophilic Z33, an innovative method with a solid-supported disulfide coupling reagent is required for the synthesis of the target compounds with prominent efficiency (29% isolated yield)...
July 20, 2016: Bioconjugate Chemistry
Cheng-Han Lin, Chen-Hsun Tsai, Ching-Tung Yeh, Jui-Lin Liang, Wan-Chun Hung, Forn-Chia Lin, Wei-Lun Chang, Hao-Yi Li, Yun-Chin Yao, Tai-I Hsu, Yu-Cheng Lee, Yi-Ching Wang, Bor-Shyang Sheu, Wu-Wei Lai, Marcus J Calkins, Michael Hsiao, Pei-Jung Lu
Concurrent chemoradiation therapy (CCRT) is the predominant treatment in esophageal cancer, however resistance to therapy and tumor recurrence are exceedingly common. Elevated ERBB2/Her2 may be at least partially responsible for both the high rates of recurrence and resistance to CCRT. This receptor tyrosine kinase is upregulated in 10-20% of esophageal squamous cell carcinoma (ESCC) tissues, and amplification of ERBB2 has been correlated with poor prognosis in esophageal cancer. Tissues from 131 ESCC patients, along with cell and animal models of the disease were used to probe the underlying mechanisms by which ERBB2 upregulation occurs and causes negative outcomes in ESCC...
May 18, 2016: Oncotarget
Xin Li, Jinmei Xu, Xi Tang, Yilun Liu, Xiaoping Yu, Zhi Wang, Weihua Liu
Trastuzumab (Herceptin®) is a recombinant humanized monoclonal antibody that is targeted against the human epidermal growth factor receptor 2 (HER2) tyrosine kinase receptor. Trastuzumab has been successfully used to treat patients with HER2-positive breast cancer, which accounts for ~25% of invasive breast cancer. However, the majority of patients who initially respond to trastuzumab demonstrate disease progression within 1 year of treatment. Therefore, identifying alternative drugs that overcome trastuzumab resistance and target HER2 may increase the magnitude and duration of response...
May 2016: Molecular Medicine Reports
Dongsheng Huang, Hongying Duan, Hao Huang, Xiangmin Tong, Yong Han, Guoqing Ru, Like Qu, Chengchao Shou, Zhongsheng Zhao
Cisplatin remains to be primary chemotherapeutic drug for gastric cancer patients, especially for advanced stage ones. However, primary or acquired resistance often occurs with the mechanisms being not well understood, which results in relapse of the cancer and poor survival. Herein, we found that HER2 upregulation was associated with cisplatin resistance. We observed that cisplatin-resistant gastric cancer cells underwent a morphological change similar to epithelial-mesenchymal transition (EMT) which is mediated by HER2 overexpression...
2016: Scientific Reports
Wei-Ming Li, Chih-Sheng Chiang, Wei-Chen Huang, Chia-Wei Su, Min-Yu Chiang, Jian-Yi Chen, San-Yuan Chen
We developed a surfactant-free method utilizing amifostine to stably link a targeting ligand (Herceptin) to amphiphilic gelatin (AG)-iron oxide@calcium phosphate (CaP) nanoparticles with hydrophobic curcumin (CUR) and hydrophilic doxorubicin (DOX) encapsulated in the AG core and CaP shell (AGIO@CaP-CD), respectively. This multi-functional nanoparticle system has a pH-sensitive CaP shell and degradable amphiphilic gelatin (AG) core, which enables controllable sequential release of the two drugs. The dual-targeting system of AGIO@CaP-CD (HER-AGIO@CaP-CD) with a bioligand and magnetic targeting resulted in significantly elevated cellular uptake in HER2-overexpressing SKBr3 cells and more efficacious therapy than delivery of targeting ligand alone due to the synergistic cell multi-drug resistance/apoptosis-inducing effect of the CUR and DOX combination...
December 28, 2015: Journal of Controlled Release: Official Journal of the Controlled Release Society
Eva J Razumienko, Jason C Chen, Zhongli Cai, Conrad Chan, Raymond M Reilly
UNLABELLED: One mechanism of resistance to trastuzumab in human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) is increased epidermal growth factor receptor (EGFR) expression. We have developed (111)In-labeled bispecific radioimmunoconjugates (bsRICs) that bind HER2 and EGFR on BC cells by linking trastuzumab Fab fragments through a polyethylene glycol (PEG24) spacer to epidermal growth factor (EGF). We hypothesized that tumors coexpressing HER2 and EGFR could be treated by dual-receptor-targeted radioimmunotherapy with these bsRICs labeled with the β-particle emitter (177)Lu or the Auger electron-emitter (111)In...
March 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Jessica L Brusgard, Moran Choe, Saranya Chumsri, Keli Renoud, Alexander D MacKerell, Marius Sudol, Antonino Passaniti
Intratumoral heterogeneity and treatment resistance drive breast cancer (BC) metastasis and recurrence. The RUNX2 transcription factor is upregulated in early stage luminal BC. However, the precise mechanism by which RUNX2 regulates an oncogenic phenotype in luminal BCs remains an enigma. We show that RUNX2 is predictive of poor overall survival in BC patients. RUNX2 associated with the TAZ transcriptional co-activator to promote a tumorigenic phenotype that was inhibited by knockdown of TAZ. RUNX2 increased endogenous TAZ translocation to the nucleus, which was prevented by inhibiting RUNX2...
September 29, 2015: Oncotarget
Xuejing Yao, Jing Jiang, Xin Wang, Changjiang Huang, Dong Li, Kuan Xie, Qiaoyu Xu, Hongwen Li, Zhuanglin Li, Liguang Lou, Jianmin Fang
Human epidermal growth factor receptor-2 (HER2) is a validated therapeutic target for breast cancer and trastuzumab (Herceptin), a humanized anti-HER2 antibody, has significant anti-cancer effects in the clinic. However, breast cancer patients often experience disease progression after prolonged Herceptin treatment. To develop a more effective therapy, we generated humanized monoclonal antibody hertuzumab and hertuzumab-drug conjugates as novel breast cancer therapies. The hertuzumab was conjugated with small molecule cytotoxic agents monomethylauristatin E (MMAE) or monomethylauristatin F (MMAF) with various linkers to generate antibody-drug conjugates (ADCs), which were evaluated for their in vitro and in vivo anti-cancer activities...
August 2015: Breast Cancer Research and Treatment
Ashok K Chakraborty, Cynthia Zerillo, Michael P DiGiovanna
The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models...
August 2015: Breast Cancer Research and Treatment
Chandini Thirukkumaran, Don G Morris
Current mainstays in cancer treatment such as chemotherapy, radiation therapy, hormonal manipulation, and even targeted therapies such as Trastuzumab (herceptin) for breast cancer or Iressa (gefitinib) for non-small cell lung cancer among others are limited by lack of efficacy, cellular resistance, and toxicity. Dose escalation and combination therapies designed to overcome resistance and increase efficacy are limited by a narrow therapeutic index. Oncolytic viruses are one such group of new biological therapeutics that appears to have a wide spectrum of anticancer activity with minimal human toxicity...
2015: Methods in Molecular Biology
Sanjeevani Arora, Erica A Golemis
HER2-positive breast cancers that have become resistant to HER2-targeting agents, such as trastuzumab (also known as Herceptin), have limited treatment options. In this issue of Science Signaling, Singh et al. have identified a characteristic increase in the endoplasmic reticulum (ER)-associated degradation (ERAD) system in HER2-positive tumors as a mechanism of relieving proteotoxic stress. Synthetic lethality arising from targeted disruption of ERAD signaling in conjunction with other HER2-dependent signaling may improve therapeutic management of this difficult class of breast tumors...
May 26, 2015: Science Signaling
Elham Arkan, Reza Saber, Ziba Karimi, Mojtaba Shamsipur
A highly sensitive impedimetric immunosensor based on a gold nanoparticles/multiwall carbon nanotube-ionic liquid electrode (AuNPs/MW-CILE) was developed for the determination of human epidermal growth factor receptor 2 (HER2). Gold nanoparticles were used to enhance the extent of immobilization and to retain the immunoactivity of the antibody Herceptin on the electrode. Cyclic voltammetry and electrochemical impedance spectroscopy were employed for characterization of various layers coated onto the AuNPs/MW-CILE...
May 18, 2015: Analytica Chimica Acta
Swapnil S Desale, Srikumar M Raja, Jong Oh Kim, Bhopal Mohapatra, Kruti S Soni, Haitao Luan, Stetson H Williams, Timothy A Bielecki, Dan Feng, Matthew Storck, Vimla Band, Samuel M Cohen, Hamid Band, Tatiana K Bronich
ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin™; Genentech), with chemotherapy is the current standard of treatment. Novel agents and strategies continue to be explored, given the challenges posed by Trastuzumab-resistance development in most patients. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which induces ErbB2 degradation and attenuates downstream oncogenic signaling, is one such agent that showed significant promise in early phase I and II clinical trials...
June 28, 2015: Journal of Controlled Release: Official Journal of the Controlled Release Society
Nicole A Doudican, Ansu Kumar, Neeraj Kumar Singh, Prashant R Nair, Deepak A Lala, Kabya Basu, Anay A Talawdekar, Zeba Sultana, Krishna Kumar Tiwari, Anuj Tyagi, Taher Abbasi, Shireen Vali, Ravi Vij, Mark Fiala, Justin King, MaryAnn Perle, Amitabha Mazumder
BACKGROUND: The personalization of cancer treatments implies the reconsideration of a one-size-fits-all paradigm. This move has spawned increased use of next generation sequencing to understand mutations and copy number aberrations in cancer cells. Initial personalization successes have been primarily driven by drugs targeting one patient-specific oncogene (e.g., Gleevec, Xalkori, Herceptin). Unfortunately, most cancers include a multitude of aberrations, and the overall impact on cancer signaling and metabolic networks cannot be easily nullified by a single drug...
2015: Journal of Translational Medicine
W L Sun, D Lan, T Q Gan, Z W Cai
UNLABELLED: Acquired multidrug resistance (MDR) is the main mechanism of chemotherapeutic drugs resistance. Nevertheless, the mechanisms of MDR are complex and still not very clear. Recently, including our previous study, several studies have revealed that macroautophagy (here referred to as autophagy) induced by anti-cancer drugs in breast cancer cells may facilitate the development of resistance to epirubicin (EPI), paclitaxel (PTX), tamoxifen or herceptin. Whereas there are a few studies on the relationship between autophagy and MDR, especially the studies designed directly employing induced resistant breast cancer cells...
2015: Neoplasma
Tao Ma, Lu Yang, Jin Zhang
Trastuzumab (Herceptin) has been widely used in breast cancer treatment. However, the majority of cancers that initially respond to trastuzumab begin to progress again within 1 year. Despite the high resistance rate, the molecular mechanisms underlying this desease are not well understood. In the present study, microRNA (miRNA‑542‑3p modulated trastuzumab resistance in SKBR3 and MCF7/Her2 breast cancer cell lines. Trastuzumab induced miRNA‑542‑3p expression in SKBR3 and MCF7/Her2 cells. Furthermore, knockdown of miRNA‑542‑3p in the two cell lines resulted in decreased drug sensitivity to trastuzumab and cell apoptosis...
March 2015: Oncology Reports
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