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TKI resistance

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https://www.readbyqxmd.com/read/28319094/targeting-c-fos-and-dusp1-abrogates-intrinsic-resistance-to-tyrosine-kinase-inhibitor-therapy-in-bcr-abl-induced-leukemia
#1
Meenu Kesarwani, Zachary Kincaid, Ahmed Gomaa, Erika Huber, Sara Rohrabaugh, Zain Siddiqui, Muhammad F Bouso, Tahir Latif, Ming Xu, Kakajan Komurov, James C Mulloy, Jose A Cancelas, H Leighton Grimes, Mohammad Azam
Tyrosine-kinase inhibitor (TKI) therapy for human cancers is not curative, and relapse occurs owing to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD stem or progenitor cells in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here we report that oncogenic kinase and growth-factor signaling converge to induce the expression of the signaling proteins FBJ osteosarcoma oncogene (c-FOS, encoded by Fos) and dual-specificity phosphatase 1 (DUSP1)...
March 20, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28316082/dacomitinib-induced-diarrhoea-is-associated-with-altered-gastrointestinal-permeability-and-disruption-in-ileal-histology-in-rats
#2
Ysabella Z A Van Sebille, Rachel J Gibson, Hannah R Wardill, Kate R Secombe, Imogen A Ball, Dorothy M K Keefe, John W Finnie, Joanne M Bowen
Dacomitinib - an irreversible pan-ErbB tyrosine kinase inhibitor (TKI) - causes diarrhoea in 75% of patients. Dacomitinib-induced diarrhoea has not previously been investigated and the mechanisms remain poorly understood. The present study aimed to develop an in-vitro and in-vivo model of dacomitinib-induced diarrhoea to investigate underlying mechanisms. T84 cells were treated with 1-4 μM dacomitinib and resistance and viability were measured using transepithelial electrical resistance (TEER) and XTT assays...
March 17, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28302223/-current-status-and-prospect-of-t790m-mutation-in-non-small-cell-lung-cancer
#3
Qin Yu, Da Jiang, Ying Li
Targeted therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) is regarded as the main accepted first-line treatment on EGFR mutation in non-small cell lung cancer (NSCLC). Although targeted therapy for the first and two generation of TKIs may lead to longer progression-free survival (PFS) and better tolerance for patients, the long-term treatment will inevitably lead to drug resistance. Among them, more than 50% of acquired resistance is associated with T790M mutation. The latest guidelines from the National Comprehensive Cancer Network (NCCN) have been proposed that the three generation of TKI (Osimertinib) can be used in first-line TKI therapy progress with detecting T790M mutations in patients...
March 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/28301600/the-hdac-inhibitor-sb939-overcomes-resistance-to-bcr-abl-kinase-inhibitors-conferred-by-the-bim-deletion-polymorphism-in-chronic-myeloid-leukemia
#4
Muhammad Rauzan, Charles T H Chuah, Tun Kiat Ko, S Tiong Ong
Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance...
2017: PloS One
https://www.readbyqxmd.com/read/28290473/phosphoproteomics-reveals-hmga1-a-ck2-substrate-as-a-drug-resistant-target-in-non-small-cell-lung-cancer
#5
Yi-Ting Wang, Szu-Hua Pan, Chia-Feng Tsai, Ting-Chun Kuo, Yuan-Ling Hsu, Hsin-Yung Yen, Wai-Kok Choong, Hsin-Yi Wu, Yen-Chen Liao, Tse-Ming Hong, Ting-Yi Sung, Pan-Chyr Yang, Yu-Ju Chen
Although EGFR tyrosine kinase inhibitors (TKIs) have demonstrated good efficacy in non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations, most patients develop intrinsic and acquired resistance. We quantitatively profiled the phosphoproteome and proteome of drug-sensitive and drug-resistant NSCLC cells under gefitinib treatment. The construction of a dose-dependent responsive kinase-substrate network of 1548 phosphoproteins and 3834 proteins revealed CK2-centric modules as the dominant core network for the potential gefitinib resistance-associated proteins...
March 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28289161/distinct-afatinib-resistance-mechanisms-identified-in-lung-adenocarcinoma-harboring-an-egfr-mutation
#6
Toshimitsu Yamaoka, Tohru Ohmori, Motoi Ohba, Satoru Arata, Yasunori Murata, Sojiro Kusumoto, Koichi Ando, Hiroo Ishida, Tsukasa Ohnishi, Yasutsuna Sasaki
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with significant responses in non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations. However, acquired resistance to reversible EGFR-TKIs remains a major obstacle. In particular, while the second-generation irreversible EGFR-TKI afatinib is currently used for treating NSCLC patients, the mechanisms underlying acquired afatinib resistance remain poorly understood. Here, heterogeneous mechanisms of acquired resistance were identified following long-term exposure to increasing doses of afatinib in EGFR mutant lung adenocarcinoma PC9 cells...
March 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28287083/brigatinib-combined-with-anti-egfr-antibody-overcomes-osimertinib-resistance-in-egfr-mutated-non-small-cell-lung-cancer
#7
Ken Uchibori, Naohiko Inase, Mitsugu Araki, Mayumi Kamada, Shigeo Sato, Yasushi Okuno, Naoya Fujita, Ryohei Katayama
Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR-TKI resistance...
March 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28286612/characterization-of-patients-with-chronic-myeloid-leukemia-unresponsive-to-tyrosine-kinase-inhibitors-who-underwent-allogeneic-hematopoietic-stem-cell-transplantation
#8
Franceli Ramos Carvalho, Joice Zuckermann, Alessandra Paz, Gustavo Fischer, Liane Esteves Daudt, Lisandra Della Costa Rigoni, Lúcia Silla, Laura Fogliatto, Simone Martins de Castro, Diogo André Pilger
Background: Tyrosine kinase inhibitors (TKIs) were the first drugs to use an intracellular signaling molecule as a therapeutic target. Unresponsiveness to TKIs limits therapeutic options, making allogeneic hematopoietic stem cell transplantation (HSCT) the only option leading to molecular remission. The aim of this study is to characterize CML patients unresponsive to first- and/or second-generation TKI therapy who underwent HSCT and to describe the main factors associated with treatment failure. Subjects and Methods: Twenty one CML patients who underwent allogeneic HSCT and had previously used first- and/or second-generation TKIs from January 2005 to May 2014...
January 1, 2017: International Journal of Hematology-oncology and Stem Cell Research
https://www.readbyqxmd.com/read/28285695/optimal-management-of-alk-positive-nsclc-progressing-on-crizotinib
#9
REVIEW
Giulio Metro, Marco Tazza, Roberta Matocci, Rita Chiari, Lucio Crinò
Crizotinib is an anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) that represents the standard first-line treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). In this setting, crizotinib has demonstrated a response rate of roughly 75% and a median progression-free survival just under one year. However, acquired resistance will emerge in virtually all crizotinib-treated patients, whose management may require a diversified approach according to the pace of the disease and/or the site(s) of disease progression...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285694/sbrt-for-oligoprogressive-oncogene-addicted-nsclc
#10
REVIEW
L Basler, S G C Kroeze, M Guckenberger
Lung cancer is one of the leading causes of cancer death in men and women and treatment outcome continues to lag behind other common cancer types. A subset of lung adenocarcinoma patients exhibit a somatic mutation in EGFR or an ALK rearrangement. In these patients, targeted TKI therapy results in higher response rates, improved PFS and reduced side effects compared with platinum-based chemotherapy. Despite initial activity of the TKIs, ultimately all patients present with disease progression after about a year on TKI therapy due to resistance development...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285689/mutations-in-tp53-pik3ca-pten-and-other-genes-in-egfr-mutated-lung-cancers-correlation-with-clinical-outcomes
#11
Paul A VanderLaan, Deepa Rangachari, Susan M Mockus, Vanessa Spotlow, Honey V Reddi, Joan Malcolm, Mark S Huberman, Loren J Joseph, Susumu S Kobayashi, Daniel B Costa
INTRODUCTION: The degree and duration of response to epidermal growth factor receptor (EGFR) inhibitors in EGFR mutated lung cancer are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors, which is currently unknown in view of the prevailing single gene assay diagnostic paradigm in clinical practice, could play a role in clinical outcomes and/or mechanisms of resistance. METHODS: We retrospectively probed our institutional lung cancer database for tumors with EGFR kinase domain mutations that were also evaluated by more comprehensive molecular profiling, and evaluated tumor response to EGFR tyrosine kinase inhibitors (TKIs)...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285685/combination-treatment-with-erlotinib-and-ampelopsin-overcomes-erlotinib-resistance-in-nsclc-cells-via-the-nox2-ros-bim-pathway
#12
Seung-Woo Hong, Nam-Sook Park, Min Hye Noh, Ju A Shim, Byul-Nim Ahn, Yeong Seok Kim, Daejin Kim, Hyun-Kyung Lee, Dae Young Hur
OBJECTIVES: Erlotinib, a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), has been shown to have a dramatic effect in non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, the presence of primary resistance or acquired resistance to EGFR-TKI is the most common reason for switching to other anti-cancer agents. Even though there are newer agents that have activity in the presence of the T790M mutation, identification of potential agents that could overcome resistance to EGFR-TKI is still needed for the treatment of NSCLC patients...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285073/development-of-an-uplc-ms-ms-method-for-quantification-of-avitinib-ac0010-and-its-five-metabolites-in-human-cerebrospinal-fluid-application-to-a-study-of-the-blood-brain-barrier-penetration-rate-of-non-small-cell-lung-cancer-patients
#13
Weicong Wang, Xin Zheng, Hanping Wang, Lu Wang, Ji Jiang, Pei Hu
Avitinib (AC0010) is a mutant-selective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), designed to be a targeted therapeutic agent for non-small cell lung cancer (NSCLC) patients harboring EGFR active and T790M resistant mutations. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of Avitinib and its five metabolites (M1, M2, M4, M7, MII-6) in human cerebrospinal fluid (CSF). The samples were purified by protein precipitation and separated on a BEH C18 column (2...
March 4, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28278729/genomic-instability-is-a-principle-pathologic-feature-of-flt3-itd-kinase-activity-in-acute-myeloid-leukemia-leading-to-clonal-evolution-and-disease-progression
#14
Melanie T Rebechi, Keith W Pratz
Acute Myeloid Leukemia with FLT3 ITD mutations are associated with a poor prognosis characterized by a higher relapse rate, shorter relapse free survival, and decreased likelihood of response to therapy at relapse. FLT3 ITD signaling drives cell proliferation and survival. FLT3 ITD AML disease progression is associated with cytogenetic evolution and acquired tyrosine kinase inhibitor (TKI) resistance suggesting a potential role of genomic instability. There is growing evidence demonstrating a relationship between FLT3 signaling and increased DNA damage, specifically through increased reactive oxygen species (ROS) resulting in double-strand breaks (DSB), as well as impaired DNA repair, involving deficiencies in the non-homologous end joining (NHEJ), alternative non-homologous end joining (ALT NHEJ) and homologous recombination (HR) pathways...
February 6, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28271729/egfr-tki-combination-with-immunotherapy-in-non-small-cell-lung-cancer
#15
Myung-Ju Ahn, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) has significantly improved clinical outcomes compared with chemotherapy in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR gene mutation. Areas covered: Almost all patients treated with EGFR TKIs eventually develop acquired resistance. It has been reported that activation of the oncogenic EGFR pathway enhances susceptibility of the lung tumors to PD-1 blockade in mouse model, suggesting combination of PD1 blockade with EGFR TKIs may be a promising therapeutic strategy...
March 8, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28266520/targeted-therapies-reversal-of-fortunes-for-tki-resistance
#16
Louise Stone
No abstract text is available yet for this article.
March 7, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28266510/kidney-cancer-reversal-of-fortunes-for-tki-resistance
#17
Louise Stone
No abstract text is available yet for this article.
March 7, 2017: Nature Reviews. Urology
https://www.readbyqxmd.com/read/28259822/ddx17-nucleocytoplasmic-shuttling-promotes-acquired-gefitinib-resistance-in-non-small-cell-lung-cancer-cells-via-activation-of-%C3%AE-catenin
#18
Kai Li, Chunfen Mo, Di Gong, Yan Chen, Zhao Huang, Yanyan Li, Jie Zhang, Lugang Huang, Yuan Li, Frances V Fuller-Pace, Ping Lin, Yuquan Wei
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations, almost all these patients will eventually develop acquired resistance to EGFR-TKI. However, the molecular mechanisms responsible for gefitinib resistance remain still not fully understood. Here, we report that elevated DDX17 levels are observed in gefitinib-resistant NSCLC cells than gefitinib-sensitive cells. Upregulation of DDX17 enhances the gefitinib resistance, whereas DDX17-silenced cells partially restore gefitinib sensitivity...
March 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28257089/blockade-of-y177-and-nuclear-translocation-of-bcr-abl-inhibits-proliferation-and-promotes-apoptosis-in-chronic-myeloid-leukemia-cells
#19
Qianyin Li, Zhenglan Huang, Miao Gao, Weixi Cao, Qin Xiao, Hongwei Luo, Wenli Feng
The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which is expressed in the nucleus can induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and rapamycin-binding protein) and FRB (the FKBP-rapamycin binding domain of the protein kinase, mTOR) mediated by AP21967, we constructed a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear...
March 2, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28247252/cabozantinib-an-active-novel-multikinase-inhibitor-in-renal-cell-carcinoma
#20
REVIEW
Nizar M Tannir, Gisela Schwab, Viktor Grünwald
Clear cell renal cell carcinoma (RCC) is characterized by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. VHL loss drives tumor angiogenesis and accounts for the clinical activity of VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs), the first-line standard of care for advanced RCC. Within the last year, three new second-line treatments have received FDA approval for use after anti-angiogenic therapy: the immune checkpoint inhibitor nivolumab, the TKI cabozantinib, and the combination of the TKI lenvatinib and the mTOR inhibitor everolimus...
February 2017: Current Oncology Reports
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