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Lapatinib resistance

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https://www.readbyqxmd.com/read/29786108/mir%C3%A2-494-inhibits-cancer%C3%A2-initiating-cell-phenotypes-and-reverses-resistance-to-lapatinib-by-downregulating-fgfr2-in-her2%C3%A2-positive-gastric-cancer
#1
Yanxia Yu, Xuejuan Yu, Hong Liu, Qingxun Song, Yongmei Yang
In gastric cancer, >15% of cases are associated with the amplification of human epidermal growth factor receptor 2 (HER2), which leads to poor clinical outcomes. Lapatinib, a potent ATP‑competitive inhibitor, is a small, orally active molecule, which inhibits the tyrosine kinases of HER2 and epidermal growth factor receptor type 1. The activation of receptor tyrosine kinases can contribute to lapatinib resistance in HER2‑positive gastric cancer. The aim of the present study was to explore the effects of miR‑494 and FGFR2 in regulation of cancer‑initiating cell phenotypes and therapeutic efficiency of lapatinib in HER2‑positive gastric cancer...
May 16, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29781317/combination-therapies-for-the-treatment-of-her2-positive-breast-cancer-current-and-future-prospects
#2
Mariana Brandão, Noam F Pondé, Francesca Poggio, Nuria Kotecki, Mauren Salis, Matteo Lambertini, Evandro de Azambuja
HER2-positive disease is an aggressive subtype of breast cancer that has been revolutionized by anti-HER2 directed therapies. Multiple drugs have been developed and are currently in clinical use, including trastuzumab, lapatinib, pertuzumab, T-DM1 and neratinib, alone or combined in "dual HER2-blockade" regimens. Areas covered: A comprehensive literature review was performed regarding the current state and the future of combination regimens containing anti-HER2 agents, focusing on their efficacy, toxicity and cost-effectiveness...
May 21, 2018: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29755619/molecularly-targeted-therapy-for-the-oral-cancer-stem-cells
#3
REVIEW
Yuichi Ohnishi, Hiroki Yasui, Masami Nozaki, Masahiro Nakajima
Human cancer tissues are heterogeneous in nature and become differentiated during expansion of cancer stem cells (CSCs). CSCs initiate tumorigenesis, and are involved in tumor recurrence and metastasis. Furthermore, data show that CSCs are highly resistant to anticancer drugs. Cetuximab, a specific anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is used in cancer treatment. Although development of resistance to cetuximab is well recognized, the underlying mechanisms remain unclear. 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...
May 2018: Japanese Dental Science Review
https://www.readbyqxmd.com/read/29751334/treatment-of-advanced-her2-positive-breast-cancer-2018-and-beyond
#4
REVIEW
Noam Pondé, Mariana Brandão, Georges El-Hachem, Emilie Werbrouck, Martine Piccart
In the 1980s the importance of HER2 signalling to the aberrant behaviour of a subset of breast cancer cells was recognized for the first time and, consequently, a hitherto unknown subtype of breast cancer - HER2-positive (HER2+) breast cancer was identified. The development of the anti-HER2 class of drugs, first with trastuzumab, followed closely by lapatinib, pertuzumab, and T-DM1, has improved outcomes dramatically. Nevertheless, metastatic HER2+ breast cancer remains an incurable disease and new therapeutic options are needed...
May 2, 2018: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29719603/gefitinib-or-lapatinib-with-foretinib-synergistically-induce-a-cytotoxic-effect-in-melanoma-cell-lines
#5
Ewelina Dratkiewicz, Katarzyna Pietraszek-Gremplewicz, Aleksandra Simiczyjew, Antonina Joanna Mazur, Dorota Nowak
Melanoma is an aggressive cancer type with a high mortality rate and an elevated resistance to conventional treatment. Recently, promising new tools for anti-melanoma targeted therapy have emerged including inhibitors directed against frequently overexpressed receptors of growth factors implicated in the progression of this cancer. The ineffectiveness of single-targeted therapy prompted us to study the efficacy of treatment with a combination of foretinib, a MET (hepatocyte growth factor receptor) inhibitor, and gefitinib or lapatinib, EGFR (epidermal growth factor receptor) inhibitors...
April 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29717218/ganetespib-targets-multiple-levels-of-the-receptor-tyrosine-kinase-signaling-cascade-and-preferentially-inhibits-erbb2-overexpressing-breast-cancer-cells
#6
Harry Lee, Nipun Saini, Erin W Howard, Amanda B Parris, Zhikun Ma, Qingxia Zhao, Ming Zhao, Bolin Liu, Susan M Edgerton, Ann D Thor, Xiaohe Yang
Although ErbB2-targeted therapeutics have significantly improved ErbB2+ breast cancer patient outcomes, therapeutic resistance remains a significant challenge. Therefore, the development of novel ErbB2-targeting strategies is necessary. Importantly, ErbB2 is a sensitive client protein of heat shock protein 90 (HSP90), which regulates client protein folding, maturation, and stabilization. HSP90 inhibition provides an alternative therapeutic strategy for ErbB2-targeted degradation. In particular, ganetespib, a novel HSP90 inhibitor, is a promising agent for ErbB2+ cancers...
May 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29712619/inhibitor-induced-her2-her3-heterodimerisation-promotes-proliferation-through-a-novel-dimer-interface
#7
Jeroen Claus, Gargi Patel, Flavia Autore, Audrey Colomba, Gregory Weitsman, Tanya N Soliman, Selene Roberts, Laura C Zanetti-Domingues, Michael Hirsch, Francesca Collu, Roger George, Elena Ortiz-Zapater, Paul R Barber, Boris Vojnovic, Yosef Yarden, Marisa L Martin-Fernandez, Angus Cameron, Franca Fraternali, Tony Ng, Peter J Parker
While targeted therapy against HER2 is an effective first-line treatment in HER2+ breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, is widely implicated in the resistance to HER2-mediated therapy. Here, we show that lapatinib, an ATP-competitive inhibitor of HER2, is able to induce proliferation cooperatively with the HER3 ligand neuregulin. This counterintuitive synergy between inhibitor and growth factor depends on their ability to promote atypical HER2-HER3 heterodimerisation...
May 1, 2018: ELife
https://www.readbyqxmd.com/read/29678476/cabazitaxel-plus-lapatinib-as-therapy-for-her2-metastatic-breast-cancer-with-intracranial-metastases-results-of-a-dose-finding-study
#8
Denise A Yardley, Lowell L Hart, Patrick J Ward, Gail L Wright, Mythili Shastry, Lindsey Finney, Laura M DeBusk, John D Hainsworth
BACKGROUND: Lapatinib is an oral small molecule tyrosine kinase epidermal growth factor receptor-1/HER2 inhibitor that crosses the blood-brain barrier and is active against central nervous system (CNS) metastases. Cabazitaxel is a taxoid that is effective against taxane-resistant metastatic breast cancer (MBC) and has distinguished itself by its ability to cross the blood-brain barrier. The present phase II study (ClinicalTrials.gov identifier, NCT01934894) evaluated the combination of these agents to treat HER2+ MBC patients with CNS metastases...
March 8, 2018: Clinical Breast Cancer
https://www.readbyqxmd.com/read/29670855/current-therapies-for-human-epidermal-growth-factor-receptor-2-positive-metastatic-breast-cancer-patients
#9
REVIEW
Alexey A Larionov
The median survival of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) has more than doubled, since the discovery of HER2-targeted treatments: it rose from less than 2 years in 2001 (prior introduction of trastuzumab) to more than 4 years in 2017. The initial generation of HER2-targeted therapies included trastuzumab with taxanes in the first line, followed by the addition of lapatinib and by a switch to another cytotoxic agent after progression. Results of CLEOPATRA, EMILIA, and TH3RESA trials have changed this clinical practice...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29596781/friends-with-benefits-microenvironmental-nrg1%C3%AE-and-hgf-mediate-her2-targeted-resistance-in-l-her2-and-her2e-breast-cancer
#10
Sarah B Crist, Cyrus M Ghajar
Watson et al. use microenvironment microarrays to assess how extrinsic signals within the tumor microenvironment influence HER2++ breast cancer resistance to the HER2-targeted tyrosine kinase inhibitor lapatinib.
March 28, 2018: Cell Systems
https://www.readbyqxmd.com/read/29574636/gpcrs-profiling-and-identification-of-gpr110-as-a-potential-new-target-in-her2-breast-cancer
#11
Raksha R Bhat, Puja Yadav, Debashish Sahay, Dharmendra K Bhargava, Chad J Creighton, Sahar Yazdanfard, Ahmed Al-Rawi, Vikas Yadav, Lanfang Qin, Sarmistha Nanda, Vidyalakshmi Sethunath, Xiaoyong Fu, Carmine De Angelis, Vihang A Narkar, C Kent Osborne, Rachel Schiff, Meghana V Trivedi
PURPOSE: G protein-coupled receptors (GPCRs) represent the largest family of druggable targets in human genome. Although several GPCRs can cross-talk with the human epidermal growth factor receptors (HERs), the expression and function of most GPCRs remain unknown in HER2+ breast cancer (BC). In this study, we aimed to evaluate gene expression of GPCRs in tumorigenic or anti-HER2 drug-resistant cells and to understand the potential role of candidate GPCRs in HER2+ BC. METHODS: Gene expression of 352 GPCRs was profiled in Aldeflur+ tumorigenic versus Aldeflur- population and anti-HER2 therapy-resistant derivatives versus parental cells of HER2+ BT474 cells...
March 24, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29550255/microenvironment-mediated-mechanisms-of-resistance-to-her2-inhibitors-differ-between-her2-breast-cancer-subtypes
#12
Spencer S Watson, Mark Dane, Koei Chin, Zuzana Tatarova, Moqing Liu, Tiera Liby, Wallace Thompson, Rebecca Smith, Michel Nederlof, Elmar Bucher, David Kilburn, Matthew Whitman, Damir Sudar, Gordon B Mills, Laura M Heiser, Oliver Jonas, Joe W Gray, James E Korkola
Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib...
February 21, 2018: Cell Systems
https://www.readbyqxmd.com/read/29522716/combined-inhibition-of-egfr-and-c-abl-suppresses-the-growth-of-fulvestrant-resistant-breast-cancer-cells-through-mir-375-autophagy-axis
#13
Lunming Liu, Weifeng Shen, Zhihui Zhu, Jinxiong Lin, Qingxia Fang, Yeping Ruan, Huajun Zhao
Fulvestrant is the FDA-approved "pure anti-estrogen" agent for malignant breast cancer therapy. But endocrine resistance causes drug failure. A new approach is desired for fulvestrant-resistant breast cancer (FRBC) therapy. This study aims to find an effective approach to inhibit FRBC for patients with advanced breast cancer. MTT assay was first performed to detect the effect of inhibitors of c-ABL (imatinib) and EGFR (lapatinib) on FRBC cells. Microarray analysis was carried out to identify microRNA which is significantly changed between parental and FRBC cells...
April 6, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29476008/coamplification-of-mir-4728-protects-her2-amplified-breast-cancers-from-targeted-therapy
#14
Konstantinos V Floros, Timothy L Lochmann, Bin Hu, Carles Monterrubio, Mark T Hughes, Jason D Wells, Cristina Bernadó Morales, Maninderjit S Ghotra, Carlotta Costa, Andrew J Souers, Sosipatros A Boikos, Joel D Leverson, Ming Tan, Violeta Serra, Jennifer E Koblinski, Joaquin Arribas, Aleix Prat, Laia Paré, Todd W Miller, Mikhail G Dozmorov, Hisashi Harada, Brad E Windle, Maurizio Scaltriti, Anthony C Faber
HER2 ( ERBB2 ) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR -mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment...
March 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29467936/dynamic-changes-in-cd44v-positive-cells-after-preoperative-anti-her2-therapy-and-its-correlation-with-pathologic-complete-response-in-her2-positive-breast-cancer
#15
Teruo Yamauchi, Jose Rodrigo Espinosa Fernandez, Chiyo K Imamura, Hideko Yamauchi, Hiromitsu Jinno, Maiko Takahashi, Yuko Kitagawa, Seigo Nakamura, Bora Lim, Savitri Krishnamurthy, James M Reuben, Diane Liu, Debasish Tripathy, Helen Chen, Naoko Takebe, Hideyuki Saya, Naoto T Ueno
Chemotherapy has been reported to increase the proportion of cancer stem cells (CSCs) and to promote epithelial-mesenchymal transition (EMT) phenotype changes. Anti-HER2 therapy may provide a strategy for eliminating CSC and EMT, which contribute to therapeutic resistance. No study has determined the changes in the quantity or characteristics of CSCs or circulating tumor cells (CTCs) with EMT phenotype during preoperative anti-HER2 therapy, and whether these changes correlate to response to dual anti-HER2 therapy...
January 23, 2018: Oncotarget
https://www.readbyqxmd.com/read/29453318/integration-of-distinct-shca-signaling-complexes-promotes-breast-tumor-growth-and-tyrosine-kinase-inhibitor-resistance
#16
Jacqueline R Ha, Ryuhjin Ahn, Harvey W Smith, Valerie Sabourin, Steven Hébert, Eduardo Cepeda Cañedo, Young Kyuen Im, Claudia L Kleinman, William J Muller, Josie Ursini-Siegel
The commonality between most phospho-tyrosine signaling networks is their shared use of adaptor proteins to transduce mitogenic signals. ShcA ( SHC1 ) is one such adaptor protein that employs two phospho-tyrosine binding domains (PTB and SH2) and key phospho-tyrosine residues to promote mammary tumorigenesis. Receptor tyrosine kinases (RTK), such as ErbB2, bind the ShcA PTB domain to promote breast tumorigenesis by engaging Grb2 downstream of the ShcA tyrosine phosphorylation sites to activate AKT/mTOR signaling...
May 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29428415/genome-scale-signatures-of-gene-interaction-from-compound-screens-predict-clinical-efficacy-of-targeted-cancer-therapies
#17
Peng Jiang, Winston Lee, Xujuan Li, Carl Johnson, Jun S Liu, Myles Brown, Jon Christopher Aster, X Shirley Liu
Identifying reliable drug response biomarkers is a significant challenge in cancer research. We present computational analysis of resistance (CARE), a computational method focused on targeted therapies, to infer genome-wide transcriptomic signatures of drug efficacy from cell line compound screens. CARE outputs genome-scale scores to measure how the drug target gene interacts with other genes to affect the inhibitor efficacy in the compound screens. Such statistical interactions between drug targets and other genes were not considered in previous studies but are critical in identifying predictive biomarkers...
March 28, 2018: Cell Systems
https://www.readbyqxmd.com/read/29409051/impact-of-genomic-alterations-on-lapatinib-treatment-outcome-and-cell-free-genomic-landscape-during-her2-therapy-in-her2-gastric-cancer-patients
#18
S T Kim, K C Banks, E Pectasides, S Y Kim, K Kim, R B Lanman, A Talasaz, J An, M G Choi, J H Lee, T S Sohn, J M Bae, S Kim, S H Park, J O Park, Y S Park, H Y Lim, N K D Kim, W Park, H Lee, A J Bass, K Kim, W K Kang, J Lee
Background: To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and methods: We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples...
April 1, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29389942/structural-investigations-on-mechanism-of-lapatinib-resistance-caused-by-her-2-mutants
#19
Sharad Verma, Sukriti Goyal, Anchala Kumari, Aditi Singh, Salma Jamal, Abhinav Grover
HER-2 belongs to the human epidermal growth factor receptor (HER) family. Via different signal transduction pathways, HER-2 regulates normal cell proliferation, survival, and differentiation. Recently, it was reported that MCF10A, BT474, and MDA-MB-231 cells bearing the HER2 K753E mutation were resistant to lapatinib. Present study revealed that HER-2 mutant K753E showed some contrasting behaviour as compared to wild, L768S and V773L HER-2 in complex with lapatinib while similar to previously known lapatinib resistant L755S HER-2 mutant...
2018: PloS One
https://www.readbyqxmd.com/read/29388072/pharmacotherapeutic-management-of-breast-cancer-in-elderly-patients-the-promise-of-novel-agents
#20
REVIEW
Catherine Terret, Chiara Russo
As its incidence increases with age, breast cancer in elderly patients takes on a growing importance in clinical oncology practice. Management decisions are challenging because there is a lack of high-quality evidence in this heterogeneous population. Epidemiological studies have shown that breast cancer mortality does not decrease substantially in the older population compared with younger adults. Recent data suggest a phenotype somewhat different from that of younger patients, also confirmed at the molecular level...
February 2018: Drugs & Aging
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