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Lapatinib resistance

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https://www.readbyqxmd.com/read/28209619/lapatinib-resistance-in-breast-cancer-cells-is-accompanied-by-phosphorylation-mediated-reprogramming-of-glycolysis
#1
Benjamin Ruprecht, Esther A Zaal, Jana Zecha, Wei Wu, Celia R Berkers, Bernhard Kuster, Simone Lemeer
HER2/ERBB2-overexpressing breast cancers targeted effectively by the small molecule kinase inhibitor lapatinib frequently acquire resistance to this drug. In this study, we employed explorative mass spectrometry to profile proteomic, kinomic, and phosphoproteomic changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for >7,800 proteins, >300 protein kinases and >15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28165387/concurrent-autophagy-inhibition-overcomes-the-resistance-of-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-in-human-bladder-cancer-cells
#2
Minyong Kang, Kyoung-Hwa Lee, Hye Sun Lee, Chang Wook Jeong, Cheol Kwak, Hyeon Hoe Kim, Ja Hyeon Ku
Despite the potential therapeutic efficacy of epithelial growth factor receptor (EGFR) inhibitors in the treatment of advanced stage bladder cancer, there currently is no clear evidence to support this hypothesis. In this study, we investigate whether the concurrent treatment of autophagy-blocking agents with EGFR inhibitors exerts synergistic anti-cancer effects in T24 and J82 human bladder cancer cells. Lapatinib and gefitinib were used as EGFR inhibitors, and bafilomycin A1 (BFA1), chloroquine (CQ) and 3-methyladenine (3-MA) were used as the pharmacologic inhibitors of autophagy activities...
February 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28158234/yes1-signaling-mediates-the-resistance-to-trastuzumab-lap-atinib-in-breast-cancer
#3
Tatsuaki Takeda, Hiromasa Yamamoto, Hirotaka Kanzaki, Ken Suzawa, Takahiro Yoshioka, Shuta Tomida, Xiaojiang Cui, Ramachandran Murali, Kei Namba, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Kazuhiko Shien, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yoshihisa Kitamura, Shinichiro Miyoshi, Toshiaki Sendo, Shinichi Toyooka
BACKGROUND: Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15-23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumab-resistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474...
2017: PloS One
https://www.readbyqxmd.com/read/28152547/neratinib-resistance-and-cross-resistance-to-other-her2-targeted-drugs-due-to-increased-activity-of-metabolism-enzyme-cytochrome-p4503a4
#4
Susan Breslin, Michelle C Lowry, Lorraine O'Driscoll
BACKGROUND: Neratinib is in Phase 3 clinical trials but, unfortunately, the development of resistance is inevitable. Here, we investigated the effects of acquired neratinib resistance on cellular phenotype and the potential mechanism of this resistance. METHODS: Neratinib-resistant variants of HER2-positive breast cancer cells were developed and their cross-resistance investigated using cytotoxicity assays. Similarly, sensitivity of trastuzumab-resistant and lapatinib-resistant cells to neratinib was assessed...
February 2, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28060735/the-natural-compound-fucoidan-from-new-zealand-undaria-pinnatifida-synergizes-with-the-erbb-inhibitor-lapatinib-enhancing-melanoma-growth-inhibition
#5
Varsha Thakur, Jun Lu, Giuseppe Roscilli, Luigi Aurisicchio, Manuela Cappelletti, Emiliano Pavoni, William Lindsey White, Barbara Bedogni
Melanoma remains one of the most aggressive and therapy-resistant cancers. Finding new treatments to improve patient outcomes is an ongoing effort. We previously demonstrated that melanoma relies on the activation of ERBB signaling, specifically of the ERBB3/ERBB2 cascade. Here we show that melanoma tumor growth is inhibited by 60% over controls when treated with lapatinib, a clinically approved inhibitor of ERBB2/EGFR. Importantly, tumor growth is further inhibited to 85% when the natural compound fucoidan from New Zealand U...
January 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28059154/abcg2-overexpressing-h460-mx20-cell-xenografts-in-athymic-nude-mice-maintained-original-biochemical-and-cytological-characteristics
#6
Wei Zhang, Zhen Chen, Likun Chen, Fang Wang, Furong Li, Xiaokun Wang, Liwu Fu
H460/MX20 are derived from large cell lung cancer H460 cell line and then transformed into ABCG2-overexpressing cells by mitoxantrone's induction, which are widely used in study of multidrug resistance (MDR) in vitro. To establish and spread the model of H460/MX20 cell xenografts, we investigated whether cell biological characteristics and the MDR phenotype were maintained in vivo model. Our results demonstrated that the cell proliferation, cell cycle, and ABCG2 expression level in xH460/MX20 cells isolated from H460/MX20 cell xenografts were similar to H460/MX20 cells in vitro...
January 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28032592/feedback-activation-of-her3-attenuates-response-to-egfr-inhibitors-in-colon-cancer-cells
#7
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/27942916/synergistic-disruption-of-er%C3%AE-her2-crosstalk-by-endoxifen-and-lapatinib-in-breast-cancer-cells
#8
James Chun Yip Chan, Pei Shi Ong, Peirong Lim, Preben Xiang Long Teng, Eric Chun Yong Chan
BACKGROUND: Despite decades of clinical success, tamoxifen therapy is complicated by inter-individual variability due to CYP450 polymorphism and resistance attributed to ERα/HER2 crosstalk. Direct administration of endoxifen shows promise in circumventing obligatory CYP450 bioactivation while maintaining efficacy. Separately, disruption of the crosstalk using probe antagonists against ERα (tamoxifen) and HER2 (e.g., lapatinib) has been explored clinically. However, the efficacy of this combination may be confounded by lapatinib, a potent inactivator of CYP3A4/5 which could negate the bioactivation of tamoxifen to the active metabolite endoxifen...
January 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27903634/distinct-receptor-tyrosine-kinase-subsets-mediate-anti-her2-drug-resistance-in-breast-cancer
#9
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...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27864115/synergistic-antitumor-activity-of-regorafenib-and-lapatinib-in-preclinical-models-of-human-colorectal-cancer
#10
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...
February 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/27825137/fgfr-signaling-maintains-a-drug-persistent-cell-population-following-epithelial-mesenchymal-transition
#11
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
#12
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...
December 15, 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
#13
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
#14
REVIEW
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
#15
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...
1, 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
#16
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
#17
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
#18
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
#19
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
#20
Andriy Marusyk, Doris P Tabassum, Michalina Janiszewska, Andrew E Place, Anne Trinh, Andrii I Rozhok, Saumyadipta Pyne, Jennifer L Guerriero, Shaokun Shu, Muhammad Ekram, Alexander Ishkin, Daniel P Cahill, Yuri Nikolsky, Timothy A Chan, Mothaffar F Rimawi, Susan Hilsenbeck, Rachel Schiff, Kent C Osborne, Antony Letai, Kornelia Polyak
Using a three-dimensional coculture model, we identified significant subtype-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells in contact with cancer-associated fibroblasts (CAF). 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
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