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TKI resistance

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https://www.readbyqxmd.com/read/29331420/dacomitinib-antagonizes-multidrug-resistance-mdr-in-cancer-cells-by-inhibiting-the-efflux-activity-of-abcb1-and-abcg2-transporters
#1
Ying-Fang Fan, Wei Zhang, Leli Zeng, Zi-Ning Lei, Chao-Yun Cai, Pranav Gupta, Dong-Hua Yang, Qingbin Cui, Zuo-Dong Qin, Zhe-Sheng Chen, Louis D Trombetta
The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Numerous mechanisms have been recognized that cause MDR, but one of the most important mechanisms is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters, through which the efflux of various anticancer drugs against their concentration gradients is powered by ATP. In recent years, small molecular tyrosine kinase inhibitors (TKIs) have been developed for treatment in various human cancers overexpressing epidermal growth factor receptor (EGFR)...
January 10, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29328407/estrogen-receptor-%C3%AE-1-activation-accelerates-resistance-to-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-in-non-small-cell-lung-cancer
#2
Shengling Fu, Changyu Liu, Quanfu Huang, Sheng Fan, Hexiao Tang, Xiangning Fu, Bo Ai, Yongde Liao, Qian Chu
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR‑TKIs) have revolutionized the treatment of patients with advanced EGFR-mutant NSCLC. However, drug resistance eventually develops in the majority of patients despite an excellent initial response. The present study aimed to investigate the mechanism of acquired resistance to EGFR-TKIs and to explore strategies to overcome the resistance to EGFR-TKIs from a gender perspective...
January 4, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29327159/efficacy-and-safety-of-third-line-molecular-targeted-therapy-in-metastatic-renal-cell-carcinoma-resistant-to-first-line-vascular-endothelial-growth-factor-receptor-tyrosine-kinase-inhibitor-and-second-line-therapy
#3
Hiroki Ishihara, Toshio Takagi, Tsunenori Kondo, Hidekazu Tachibana, Kazuhiko Yoshida, Kenji Omae, Junpei Iizuka, Hirohito Kobayashi, Kazunari Tanabe
BACKGROUND: The number of studies evaluating the efficacy and safety of third-line molecular-targeted therapy for metastatic renal cell carcinoma (mRCC) is limited. METHODS: The data for 48 patients with disease progression after first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI) and second-line targeted therapy were evaluated. Patients with prior cytokine therapy were excluded. Overall survival (OS) after first- and second-line therapy initiation was compared between patients with and without third-line therapy...
January 11, 2018: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29325035/amplicon-based-next-generation-sequencing-of-plasma-cell-free-dna-for-detection-of-driver-and-resistance-mutations-in-advanced-non-small-cell-lung-cancer
#4
N Guibert, Y Hu, N Feeney, Y Kuang, V Plagnol, G Jones, K Howarth, J F Beeler, C P Paweletz, G R Oxnard
Background: Genomic analysis of plasma cell-free DNA is transforming lung cancer care, however available assays are limited by cost, turnaround time, and imperfect accuracy. Here we study amplicon-based plasma next-generation sequencing (NGS), rather than hybrid-capture-based plasma NGS, hypothesizing this would allow sensitive detection and monitoring of driver and resistance mutations in advanced non-small cell lung cancer (NSCLC). Methods: Plasma samples from patients with NSCLC and a known targetable genotype (EGFR, ALK/ROS1 and other rare genotypes) were collected while on therapy and analyzed, blinded to tumor genotype...
January 9, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29321482/enhanced-yap-expression-leads-to-egfr-tki-resistance-in-lung-adenocarcinomas
#5
Ting-Fang Lee, Yu-Chi Tseng, Phung Anh Nguyen, Yu-Chuan Li, Chao-Chi Ho, Cheng-Wen Wu
Epidermal growth factor receptor (EGFR) mutation is prevalently expressed in lung adenocarcinoma cases and acts as one of the major driving oncogenes. EGFR tyrosine kinase inhibitors (TKIs) have been used in patients with EGFR-mutant as an effective targeted therapy in lung adenocarcinoma, but drug resistance and tumor recurrence inevitably occurs. Recently, Yes-associate protein (YAP) has been reported to promote multiple cancer cell properties, such as promoting cell proliferation, epithelial-mesenchymal transition and drug resistance...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29318404/does-alk-rearrangement-predict-favorable-response-to-the-therapy-of-bevacizumab-plus-pemetrexed-in-advanced-non-small-cell-lung-cancer-case-report-and-literature-review
#6
Zhichao Liu, Youting Bao, Butuo Li, Xindong Sun, Linlin Wang
BACKGROUND: Advanced ALK-rearranged non-small cell lung cancer (NSCLC) patients will develop acquired resistance after anaplastic lymphoma kinase (ALK) inhibitors therapies. Vascular endothelial growth factor-A (VEGF-A) production and tumor vessel formation were found to be more significantly enriched in ALK-rearrangement NSCLC than that in epidermal growth factor receptor or Kirsten rat sarcoma viral oncogene mutated NSCLC. However, the correlation between ALK rearrangement and the efficacy of bevacizumab (a recombinant humanized IgG1 monoclonal antibody targeting VEGF-A) was still elusive...
January 9, 2018: Clinical and Translational Medicine
https://www.readbyqxmd.com/read/29316665/towards-comprehension-of-the-abcb1-p-glycoprotein-role-in-chronic-myeloid-leukemia
#7
REVIEW
Raquel C Maia, Flavia C Vasconcelos, Paloma S Souza, Vivian M Rumjanek
Abstract: The introduction of imatinib (IM), a BCR-ABL1 tyrosine kinase inhibitor (TKI), has represented a significant advance in the first-line treatment of chronic myeloid leukemia (CML). However, approximately 30% of patients need to discontinue IM due to resistance or intolerance to this drug. Both resistance and intolerance have also been observed in treatment with the second-generation TKIs-dasatinib, nilotinib, and bosutinib-and the third-generation TKI-ponatinib. The mechanisms of resistance to TKIs may be BCR-ABL1-dependent and/or BCR-ABL1-independent...
January 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29315500/long-term-outcome-of-dasatinib-first-line-treatment-in-gastrointestinal-stromal-tumor-a-multicenter-2-stage-phase-2-trial-swiss-group-for-clinical-cancer-research-56-07
#8
Michael Montemurro, Angela Cioffi, Julien Dômont, Piotr Rutkowski, Arnaud D Roth, Roger von Moos, Roman Inauen, Maud Toulmonde, Roger O Burkhard, Claudio Knuesli, Sebastian Bauer, Philippe Cassier, Heike Schwarb, Axel Le Cesne, Dieter Koeberle, Daniela Bärtschi, Daniel Dietrich, Christine Biaggi, John Prior, Serge Leyvraz
BACKGROUND: Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with gastrointestinal stromal tumors (GISTs), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of BCR-ABL, KIT, and SRC family kinases as well as imatinib-resistant cells. In GISTs, response evaluation is routinely done using computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography coupled to CT (FDG-PET/CT) for early response assessment and outcome prediction...
January 9, 2018: Cancer
https://www.readbyqxmd.com/read/29312652/tyrosine-kinase-inhibitor-sensitive-pdgfr%C3%AE-mutations-in-gist-two-cases-and-review-of-the-literature
#9
Pieter A Boonstra, Jourik A Gietema, Albert J H Suurmeijer, Matthew R Groves, Fernando de Assis Batista, Ed Schuuring, Anna K L Reyners
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal malignancies of the gastrointestinal tract. Most GISTs harbor a c-KIT (80%) or a PDGFRα (10%) mutation that leads to constitutive activation of the tyrosine kinase receptor. Response to treatment with tyrosine kinase inhibitors (TKIs) is dependent on mutational status of the tumor. The most common mutation in PDGFRα, D842V, is known to be imatinib resistant. Almost all other PDGFRα mutations are imatinib sensitive. We describe two patients with a PDGFRα exon 18 mutated GIST responding to treatment with TKIs...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29312564/azacitidine-combined-with-the-selective-flt3-kinase-inhibitor-crenolanib-disrupts-stromal-protection-and-inhibits-expansion-of-residual-leukemia-initiating-cells-in-flt3-itd-aml-with-concurrent-epigenetic-mutations
#10
Anne-Kathrin Garz, Saskia Wolf, Sonja Grath, Verena Gaidzik, Stefan Habringer, Binje Vick, Martina Rudelius, Christoph Ziegenhain, Sylvia Herold, Marie-Theresa Weickert, Martha Smets, Christian Peschel, Robert A J Oostendorp, Sebastian Bultmann, Irmela Jeremias, Christian Thiede, Konstanze Döhner, Ulrich Keller, Katharina S Götze
Effectively targeting leukemia-initiating cells (LIC) in FLT3-ITD-mutated acute myeloid leukemia (AML) is crucial for cure. Tyrosine kinase inhibitors (TKI) have limited impact as single agents, failing to eradicate LIC in the bone marrow. Using primary AML samples and a patient-derived xenograft model, we investigated whether combining the FLT3-selective TKI crenolanib with the hypomethylating agent azacitidine (AZA) eliminates FLT3-ITD LIC and whether efficacy of this combination depends on co-existing mutations...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29312548/mimicking-the-bim-bh3-domain-overcomes-resistance-to-egfr-tyrosine-kinase-inhibitors-in-egfr-mutant-non-small-cell-lung-cancer
#11
Jinjing Xia, Hao Bai, Bo Yan, Rong Li, Minhua Shao, Liwen Xiong, Baohui Han
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied to treat EGFR-mutant non-small cell lung cancer (NSCLC). BIM is a BH3 domain-containing protein encoded by BCL2L11. Some EGFR-mutant NSCLC patients showing BIM deletion polymorphism are resistant to EGFR TKIs. We retrospectively investigated BIM deletion polymorphism in NSCLC patients, its correlation with EGFR TKI (erlotinib) resistance, and the mechanism underlying the drug resistance. Among 245 EGFR-mutant NSCLC patients examined, BIM deletion polymorphism was detected in 43 (12...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29299405/clinical-management-of-epidermal-growth-factor-receptor-mutation-positive-non-small-cell-lung-cancer-patients-after-progression-on-previous-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-the-necessity-of-repeated-molecular-analysis
#12
REVIEW
José Luís González-Larriba, Martín Lázaro-Quintela, Manuel Cobo, Manuel Dómine, Margarita Majem, Rosario García-Campelo
One of the most important advances in the treatment of non-small cell lung cancer (NSCLC) has been the identification of molecular alterations vulnerable to targeted inhibition, such as mutations in the epidermal growth factor receptor (EGFR) gene. EGFR tyrosine kinase inhibitors (EGFR-TKIs) are targeted agents used to treat EGFR mutation-positive advanced NSCLC showing significant improvements in terms of response rate (RR) and progression-free survival (PFS) compared to conventional chemotherapy. However, all patients eventually develop resistance to first-line EGFR-TKIs...
December 2017: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/29299123/inhibition-of-sdf-1-induced-migration-of-oncogene-driven-myeloid-leukemia-by-the-l-rna-aptamer-spiegelmer-nox-a12-and-potentiation-of-tyrosine-kinase-inhibition
#13
Ellen L Weisberg, Martin Sattler, Abdel Kareem Azab, Dirk Eulberg, Anna Kruschinski, Paul W Manley, Richard Stone, James D Griffin
Resistance to targeted tyrosine kinase inhibitors (TKI) remains a challenge for the treatment of myeloid leukemias. Following treatment with TKIs, the bone marrow microenvironment has been found to harbor a small pool of surviving leukemic CD34+ progenitor cells. The long-term survival of these leukemic cells has been attributed, at least in part, to the protective effects of bone marrow stroma. We found that the NOX-A12 'Spiegelmer', an L-enantiomeric RNA oligonucleotide that inhibits SDF-1α, showed in vitro and in vivo activity against BCR-ABL- and FLT3-ITD-dependent leukemia cells...
December 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/29298799/targeting-her2-aberrations-in-non-small-cell-lung-cancer-with-osimertinib
#14
Shengwu Liu, Shuai Li, Josephine Hai, Xiaoen Wang, Ting Chen, Max M Quinn, Peng Gao, Yanxi Zhang, Hongbin Ji, Darren Cross, Kwok-Kin Wong
PURPOSE: HER2 (or ERBB2) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2-6 percent of lung adenocarcinomas. HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). However, due to limited preclinical studies and clinical trials, currently there is still no available standard of care for lung cancer patients with HER2 aberrations. To fulfill the clinical need for targeting HER2 in non-small cell lung cancer (NSCLC) patients, we performed a comprehensive pre-clinical study to evaluate the efficacy of a third-generation TKI, osimertinib (AZD9291)...
January 3, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29296194/changes-in-pd-l1-expression-according-to-tumor-infiltrating-lymphocytes-of-acquired-egfr-tki-resistant-egfr-mutant-non-small-cell-lung-cancer
#15
Tae-Jung Kim, Soon Auck Hong, Okran Kim, Seung Joon Kim, Ji-Hyun Yang, Eun Kyo Joung, Jin-Hyoung Kang, Sook-Hee Hong
Backgrounds: EGFR-mutant non-small cell lung cancer (NSCLC) that developed acquired resistance to EGFR-tyrosine kinase (TKI) are potential candidates for programmed death 1 (PD1) inhibitor. Results: TPS≥1% for PD-L1 and low CD8 + TIL in post-TKI tumor showed a trend for a lower PFS of EGFR-TKIs (14.2 vs 9.9 months; P = 0.060) (cohort A). Only 2 of 22 specimens (9.1%) with an acquired EGFR exon 20 T790M mutation exhibited in post-TKI TPS≥50% for PD-L1. The degree in post-TKI tumor of PD-L1 expression was varied in 19 patients (40...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29290257/primary-resistance-to-osimertinib-due-to-sclc-transformation-issue-of-t790m-determination-on-liquid-re-biopsy
#16
R Minari, P Bordi, M Del Re, F Facchinetti, F Mazzoni, F Barbieri, A Camerini, C E Comin, L Gnetti, C Azzoni, R Nizzoli, B Bortesi, E Rofi, P Petreni, N Campanini, G Rossi, R Danesi, M Tiseo
OBJECTIVES: EGFR T790M mutation is the most common mechanism of resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) and could be overcome by third-generation EGFR-TKIs, such as osimertinib. Liquid biopsy, a non-invasive technique used to test the presence of the resistant mutation, may help avoiding tissue re-biopsy. However, analysing only circulating-free DNA, information about other less frequent and coexisting resistance mechanisms may remain unrevealed...
January 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29285266/characterization-of-the-efficacies-of-osimertinib-and-nazartinib-against-cells-expressing-clinically-relevant-epidermal-growth-factor-receptor-mutations
#17
Keita Masuzawa, Hiroyuki Yasuda, Junko Hamamoto, Shigenari Nukaga, Toshiyuki Hirano, Ichiro Kawada, Katsuhiko Naoki, Kenzo Soejima, Tomoko Betsuyaku
Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) were developed to overcome EGFR T790M-mediated resistance to first- and second-generation EGFR-TKIs. Third-generation EGFR-TKIs, such as osimertinib and nazartinib, are effective for patients with the EGFR T790M mutation. However, there are no direct comparison data to guide the selection of a third-generation EGFR-TKI for patients with different EGFR mutations. We previously established an in vitro model to estimate the therapeutic windows of EGFR-TKIs by comparing their relative efficacies against cells expressing mutant or wild type EGFRs...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29285237/outcome-of-egfr-mutated-nsclc-patients-with-met-driven-resistance-to-egfr-tyrosine-kinase-inhibitors
#18
Simon Baldacci, Julien Mazieres, Pascale Tomasini, Nicolas Girard, Florian Guisier, Clarisse Audigier-Valette, Isabelle Monnet, Marie Wislez, Maurice Pérol, Pascal Dô, Eric Dansin, Charlotte Leduc, Etienne Giroux Leprieur, Denis Moro-Sibilot, David Tulasne, Zoulika Kherrouche, Julien Labreuche, Alexis B Cortot
Background: Several mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC have been described including the T790M mutation and MET amplification. Whereas T790M mutation confers prolonged survival and sensitivity to 3rd generation TKIs, data are lacking on clinical features and outcome of MET-driven resistant EGFR-mutated NSCLC patients. Methods: Patients with metastatic EGFR-mutated NSCLC displaying high MET overexpression or MET amplification, detected on a biopsy performed after progression on EGFR TKI, were identified in 15 centers...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29259014/er-stress-signaling-promotes-the-survival-of-cancer-persister-cells-tolerant-to-egfr-tyrosine-kinase-inhibitors
#19
Hideki Terai, Shunsuke Kitajima, Danielle S Potter, Yusuke Matsui, Laura Gutierrez Quiceno, Ting Chen, Tae-Jung Kim, Maria Rusan, Tran C Thai, Federica Piccioni, Katherine A Donovan, Nicholas Kwiatkowski, Kunihiko Hinohara, Guo Wei, Nathanael S Gray, Eric S Fischer, Kwok-Kin Wong, Teppei Shimamura, Anthony Letai, Peter S Hammerman, David A Barbie
An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells which survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways...
December 19, 2017: Cancer Research
https://www.readbyqxmd.com/read/29249325/outcomes-in-patients-with-non-small-cell-lung-cancer-and-acquired-thr790met-mutation-treated-with-osimertinib-a-genomic-study
#20
Chia-Chi Lin, Jin-Yuan Shih, Chong-Jen Yu, Chao-Chi Ho, Wei-Yu Liao, Jih-Hsing Lee, Tzu-Hsiu Tsai, Kang-Yi Su, Min-Shu Hsieh, Yih-Leong Chang, Ya-Ying Bai, Derek De-Rui Huang, Kenneth S Thress, James Chih-Hsin Yang
BACKGROUND: Osimertinib is approved for the treatment of non-small-cell lung cancer in patients who develop the EGFR Thr790Met mutation after treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). We assessed outcomes in patients with non-small-cell lung cancer and the EGFR Thr790Met mutation who were treated with osimertinib, a third-generation EGFR TKI, after previous treatment failure with one or more other EGFR TKIs. METHODS: Eligible patients had been enrolled at one centre in the AURA study, had shown resistance to a previous EGFR TKI, and had EGFR-activating mutations and acquired Thr790Met mutation detectable in tumour tissue or plasma...
December 14, 2017: Lancet Respiratory Medicine
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