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https://www.readbyqxmd.com/read/27903634/distinct-receptor-tyrosine-kinase-subsets-mediate-anti-her2-drug-resistance-in-breast-cancer
#1
Peter B Alexander, Rui Chen, Chang Gong, Lifeng Yuan, Jeff S Jasper, Yi Ding, Geoffrey J Markowitz, Pengyuan Yang, Xin Xu, Donald P McDonnell, Erwei Song, Xiao-Fan Wang
Targeted inhibitors of the human epidermal growth factor receptor 2 (HER2) such as trastuzumab and lapatinib are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast cancers. However, approximately half of those patients either do not respond to these therapies or develop secondary resistance. Although a few signaling pathways have been implicated, a comprehensive understanding of mechanisms underlying HER2 inhibitor drug resistance is still lacking...
November 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27864115/synergistic-antitumor-activity-of-regorafenib-and-lapatinib-in-preclinical-models-of-human-colorectal-cancer
#2
Wen-Ji Zhang, Yong Li, Meng-Ning Wei, Yao Chen, Jian-Ge Qiu, Qi-Wei Jiang, Yang Yang, Di-Wei Zheng, Wu-Ming Qin, Jia-Rong Huang, Kun Wang, Wen-Juan Zhang, Yi-Jun Wang, Dong-Hua Yang, Zhe-Sheng Chen, Zhi Shi
Regorafenib significantly prolongs overall survival in patients with metastatic colorectal cancer (mCRC), but the overall clinical efficacy of regorafenib remains quite limited. Combination chemotherapy is a potentially promising approach to enhance anticancer activity, overcome drug resistance, and improve disease-free and overall survival. The current study investigates the antitumor activity of regorafenib in combination with lapatinib in preclinical models of human CRC. Our results show improved antitumor efficacy when regorafenib is combined with lapatinib both in vitro and in vivo...
November 15, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27825137/fgfr-signaling-maintains-a-drug-persistent-cell-population-following-epithelial-mesenchymal-transition
#3
Wells S Brown, Saeed Salehin Akhand, Michael K Wendt
An emerging characteristic of drug resistance in cancer is the induction of epithelial-mesenchymal transition (EMT). However, the mechanisms of EMT-mediated drug resistance remain poorly defined. Therefore, we conducted long-term treatments of human epidermal growth factor receptor-2 (Her2)-transformed breast cancer cells with either the EGFR/Her2 kinase inhibitor, Lapatinib or TGF-β, a known physiological inducer of EMT. Both of these treatment regimes resulted in robust EMT phenotypes, but upon withdrawal a subpopulation of TGF-β induced cells readily underwent mesenchymal-epithelial transition, where as Lapatinib-induced cells failed to reestablish an epithelial population...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27797970/molecular-pathways-maintaining-mapk-inhibitor-sensitivity-by-targeting-nonmutational-tolerance
#4
Michael P Smith, Claudia Wellbrock
Targeting hyperactive MAPK signaling has proven to be an effective treatment for a variety of different cancers. Responses to the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitors trametinib and cobimetinib are, however, transient, and complete remission is rarely observed; rather, outgrowth of resistant clones within progressed tumors appears inevitable. These resistant tumors display great heterogeneity, which poses a major challenge to any salvage therapy. Recent focus has, therefore, been on the early dynamics of inhibitor response during tumor regression...
October 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
#5
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/27726101/lapatinib-resistance-in-her2-cancers-latest-findings-and-new-concepts-on-molecular-mechanisms
#6
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
https://www.readbyqxmd.com/read/27708243/jwa-down-regulates-her2-expression-via-c-cbl-and-induces-lapatinib-resistance-in-human-gastric-cancer-cells
#7
Ling Ma, Weiyou Zhu, Qiang Wang, Fengming Yang, Jing Qian, Tongpeng Xu, Shouyu Wang, Jianwei Zhou, Yongqian Shu
Human epidermal growth factor receptor 2 (HER2) targeted therapy is currently considered as the standard treatment for HER2-positive advanced gastric cancer (GC). However, unsatisfactory results of recent phase III clinical trials involving lapatinib suggested biomarkers for selection of patients. The aim of this study was to identify JWA as a biomarker for lapatinib resistance in GC cells and elucidate the underlying mechanisms. Lapatinib was effective to the intrinsic cisplatin-resistant GC cells. JWA activation conferred lapatinib unresponsiveness, but reversed cisplatin resistance in GC cells...
September 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/27697991/dual-characteristics-of-novel-her2-kinase-domain-mutations-in-response-to-her2-targeted-therapies-in-human-breast-cancer
#8
Wen-Jia Zuo, Yi-Zhou Jiang, Yu-Jie Wang, Xiao-En Xu, Xin Hu, Guang-Yu Liu, Jiong Wu, Gen-Hong Di, Ke-Da Yu, Zhi-Ming Shao
PURPOSE: Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor 2 (HER2) may be an alternative mechanism to HER2 activation and can affect the sensitivity toward HER2-targeted therapies. We aimed to investigate the prevalence, clinicopathologic characteristics, and functional relevance of novel HER2 mutations in breast cancer. EXPERIMENTAL DESIGN: We performed Sanger sequencing of all exons of the HER2 gene in 1,248 primary tumors and 18 paired metastatic samples...
October 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27694691/interleukin-6-expression-contributes-to-lapatinib-resistance-through-maintenance-of-stemness-property-in-her2-positive-breast-cancer-cells
#9
Wei-Chien Huang, Chao-Ming Hung, Ching-Ting Wei, Tsung-Ming Chen, Pei-Hsuan Chien, Hsiao-Lin Pan, Yueh-Ming Lin, Yun-Ju Chen
Lapatinib is an inhibitor of human epidermal growth factor receptor 2 (HER2), which is overexpressed in 20-25% of breast cancers. Clinically, lapatinib has shown promising benefits for HER2-positive breast cancer patients; however, patients eventually acquire resistance, limiting its long-term use. In a previous study, we found that interleukin-6 (IL-6) production was increased in acquired lapatinib-resistant HER2-positive breast cancer cells. In the present study, we confirmed that lapatinib-resistant cells had elevated IL-6 expression and also maintained both stemness population and property...
September 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27687302/pathway-level-alterations-rather-than-mutations-in-single-genes-predict-response-to-her2-targeted-therapies-in-the-neo-altto-trial
#10
W Shi, T Jiang, P Nuciforo, C Hatzis, E Holmes, N Harbeck, C Sotiriou, L Peña, S Loi, D D Rosa, S Chia, A Wardley, T Ueno, J Rossari, H Eidtmann, A Armour, M Piccart-Gebhart, D L Rimm, J Baselga, L Pusztai
BACKGROUND: We performed whole-exome sequencing of pretreatment biopsies and examined whether genome-wide metrics of overall mutational load, clonal heterogeneity or alterations at variant, gene, and pathway levels are associated with treatment response and survival. PATIENTS AND METHODS: Two hundred and three biopsies from the NeoALTTO trial were analyzed. Mutations were called with MuTect, and Strelka, using pooled normal DNA. Associations between DNA alterations and outcome were evaluated by logistic and Cox-proportional hazards regression...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27678331/ibrutinib-inhibits-erbb-receptor-tyrosine-kinases-and-her2-amplified-breast-cancer-cell-growth
#11
Jun Chen, Taisei Kinoshita, Juthamas Sukbuntherng, Betty Y Chang, Laurence Elias
Ibrutinib is a potent, small-molecule Bruton tyrosine kinase (BTK) inhibitor developed for the treatment of B-cell malignancies. Ibrutinib covalently binds to Cys481 in the ATP-binding domain of BTK. This cysteine residue is conserved among 9 other tyrosine kinases, including HER2 and EGFR, which can be targeted. Screening large panels of cell lines demonstrated that ibrutinib was growth inhibitory against some solid tumor cells, including those inhibited by other HER2/EGFR inhibitors. Among sensitive cell lines, breast cancer lines with HER2 overexpression were most potently inhibited by ibrutinib (<100 nmol/L); in addition, the IC50s were lower than that of lapatinib and dacomitinib...
December 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27671678/spatial-proximity-to-fibroblasts-impacts-molecular-features-and-therapeutic-sensitivity-of-breast-cancer-cells-influencing-clinical-outcomes
#12
Andriy Marusyk, Doris Tabassum, Michalina Janiszewska, Andrew Place, Anne Trinh, Andrii I Rozhok, Saumyadipta Pyne, Jennifer Guerriero, Shaokun Shu, Muhammad Ekram, Alexander Ishkin, Daniel P Cahill, Yuri Nikolsky, Timothy A Chan, Mothaffar F Rimawi, Susan G Hilsenbeck, Rachel Schiff, C Kent Osborne, Anthony Letai, Kornelia Polyak
Using a 3D co-culture model, we identified significant sub-type-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells in contact with cancer-associated fibroblasts (CAFs). CAF-induced gene expression signatures predicted clinical outcome and immune-related differences in the microenvironment. We found that fibroblasts strongly protect carcinoma cells from lapatinib, attributable to its reduced accumulation in carcinoma cells and an elevated apoptotic threshold...
September 26, 2016: Cancer Research
https://www.readbyqxmd.com/read/27659302/a-bead-based-western-for-high-throughput-cellular-signal-transduction-analyses
#13
Fridolin Treindl, Benjamin Ruprecht, Yvonne Beiter, Silke Schultz, Anette Döttinger, Annette Staebler, Thomas O Joos, Simon Kling, Oliver Poetz, Tanja Fehm, Hans Neubauer, Bernhard Kuster, Markus F Templin
Dissecting cellular signalling requires the analysis of large number of proteins. The DigiWest approach we describe here transfers the western blot to a bead-based microarray platform. By combining gel-based protein separation with immobilization on microspheres, hundreds of replicas of the initial blot are created, thus enabling the comprehensive analysis of limited material, such as cells collected by laser capture microdissection, and extending traditional western blotting to reach proteomic scales. The combination of molecular weight resolution, sensitivity and signal linearity on an automated platform enables the rapid quantification of hundreds of specific proteins and protein modifications in complex samples...
September 23, 2016: Nature Communications
https://www.readbyqxmd.com/read/27633099/lapatinib-resistant-cancer-cells-possessing-epithelial-cancer-stem-cell-properties-develop-sensitivity-during-sphere-formation-by-activation-of-the-erbb-akt-cyclin%C3%A2-d2-pathway
#14
Yuichi Ohnishi, Hiroki Yasui, Kenji Kakudo, Masami Nozaki
Lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR)/ErbB2, has antiproliferative effects and is used to treat patients with ErbB2-positive metastatic breast cancer. In the present study, we examined the effects of lapatinib on growth of oral and prostate cancer cells. Oral squamous cell carcinoma (OSCC) cell lines HSC3, HSC4 and Ca9-22 were sensitive to the antiproliferative effects of lapatinib in anchorage-dependent culture, but the OSCC cell lines KB and SAS and the prostate cancer cell line DU145 were resistant to lapatinib...
September 7, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27599579/impact-of-the-putative-cancer-stem-cell-markers-and-growth-factor-receptor-expression-on-the-sensitivity-of-ovarian-cancer-cells-to-treatment-with-various-forms-of-small-molecule-tyrosine-kinase-inhibitors-and-cytotoxic-drugs
#15
Soozana Puvanenthiran, Sharadah Essapen, Alan M Seddon, Helmout Modjtahedi
Increased expression and activation of human epidermal growth factor receptor (EGFR) and HER-2 have been reported in numerous cancers. The aim of this study was to determine the sensitivity of a large panel of human ovarian cancer cell lines (OCCLs) to treatment with various forms of small molecule tyrosine kinase inhibitors (TKIs) and cytotoxic drugs. The aim was to see if there was any association between the protein expression of various biomarkers including three putative ovarian cancer stem cell (CSC) markers (CD24, CD44, CD117/c-Kit), P-glycoprotein (P-gp), and HER family members and response to treatment with these agents...
September 5, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27558154/identification-of-therapeutic-targets-applicable-to-clinical-strategies-in-ovarian-cancer
#16
Marianne K Kim, Natasha Caplen, Sirisha Chakka, Lidia Hernandez, Carrie House, Georgios Pongas, Elizabeth Jordan, Christina M Annunziata
BACKGROUND: shRNA-mediated lethality screening is a useful tool to identify essential targets in cancer biology. Ovarian cancer (OC) is extremely heterogeneous and most cases are advanced stages at diagnosis. OC has a high response rate initially, but becomes resistant to standard chemotherapy. We previously employed high throughput global shRNA sensitization screens to identify NF-kB related pathways. Here, we re-analyzed our previous shRNA screens in an unbiased manner to identify clinically applicable molecular targets...
August 24, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27490093/context-specific-functional-module-based-drug-efficacy-prediction
#17
Woochang Hwang, Jaejoon Choi, Mijin Kwon, Doheon Lee
BACKGROUND: It is necessary to evaluate the efficacy of individual drugs on patients to realize personalized medicine. Testing drugs on patients in clinical trial is the only way to evaluate the efficacy of drugs. The approach is labour intensive and requires overwhelming costs and a number of experiments. Therefore, preclinical model system has been intensively investigated for predicting the efficacy of drugs. Current computational drug sensitivity prediction approaches use general biological network modules as their prediction features...
2016: BMC Bioinformatics
https://www.readbyqxmd.com/read/27489862/durable-response-of-glioblastoma-to-adjuvant-therapy-consisting-of-temozolomide-and-a-weekly-dose-of-amd3100-plerixafor-a-cxcr4-inhibitor-together-with-lapatinib-metformin-and-niacinamide
#18
Adan Rios, Sigmund H Hsu, Angel Blanco, Jamie Buryanek, Arthur L Day, Mary F McGuire, Robert E Brown
UNLABELLED: Glioblastoma multiforme (GBM) is a CNS (central nervous system) malignancy with a low cure rate. Median time to progression after standard treatment is 7 months and median overall survival is 15 months [1]. Post-treatment vasculogenesis promoted by recruitment of bone marrow derived cells (BMDCs, CD11b+ myelomonocytes) is one of main mechanisms of GBM resistance to initial chemoradiotherapy treatment [2]. Local secretion of SDF-1, cognate ligand of BMDCs CXCR4 receptors attracts BMDCs to the post-radiation tumor site...
2016: Oncoscience
https://www.readbyqxmd.com/read/27475932/irreversible-inhibition-of-%C3%AE-16her2-is-necessary-to-suppress-%C3%AE-16her2-positive-breast-carcinomas-resistant-to-lapatinib
#19
Martina Tilio, Valentina Gambini, Junbiao Wang, Chiara Garulli, Cristina Kalogris, Cristina Andreani, Caterina Bartolacci, Maria Elexpuru Zabaleta, Lucia Pietrella, Albana Hysi, Manuela Iezzi, Barbara Belletti, Fiorenza Orlando, Mauro Provinciali, Roberta Galeazzi, Cristina Marchini, Augusto Amici
HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Δ16HER2 splice variant commonly coexpressed with HER2 and identified as a clinically important HER2 molecular alteration promoting aggressive metastatic breast cancer. Consistently, mice transgenic for the human Δ16HER2 isoform (Δ16HER2 mice) develop invasive mammary carcinomas with early onset and 100% penetrance. The present study provides preclinical evidence that Δ16HER2 expression confers de novo resistance to standard anti-HER2-therapies such as Lapatinib and acquired resistance to the selective Src inhibitor Saracatinib in breast cancer...
October 10, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27474152/erbb2-overexpression-establishes-erbb3-dependent-hypersensitivity-of-breast-cancer-cells-to-withaferin-a
#20
Wenjun Liu, Annalise R Barnette, Samita Andreansky, Ralf Landgraf
The catalytically deficient ERBB3 strongly synergizes with the receptor tyrosine kinase ERBB2, and elevated levels represent an overall risk factor for unfavorable disease outcomes in breast cancer. Although itself not a target of pan-ERBB kinase inhibitors, it contributes to resistance in ERBB2-targeted treatment regiments. The steroidal lactone Withaferin A (WA) has established broad anticancer properties through several modes of action and was shown to be effective against triple-negative breast cancers at elevated concentrations...
July 29, 2016: Molecular Cancer Therapeutics
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