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T790m and met

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https://www.readbyqxmd.com/read/28521430/reduced-expression-levels-of-pten-are-associated-with-decreased-sensitivity-of-hcc827-cells-to-icotinib
#1
Yang Zhai, Yanjun Zhang, Kejun Nan, Xuan Liang
The clinical resistance of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been linked to EGFR T790M resistance mutations or MET amplifications. Additional mechanisms underlying EGFR-TKI drug resistance remain unclear. The present study demonstrated that icotinib significantly inhibited the proliferation and increased the apoptosis rate of HCC827 cells; the cellular mRNA and protein expression levels of phosphatase and tensin homolog (PTEN) were also significantly downregulated...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28515244/what-when-and-how-of-biomarker-testing-in-non-small-cell-lung-cancer
#2
Gregory L Riely
Biomarker testing is recommended for all patients diagnosed with non-small cell lung cancer. At a minimum, testing should include the mutations/fusions EGFR, ALK, ROS1, and the protein programmed death ligand-1 (PD-L1), because FDA-approved therapies are available for these alterations. Other actionable molecular findings include RET rearrangements, BRAF(V600E) mutations, and MET exon 14 alterations. If adequate testing was not performed at treatment initiation, molecular testing should be performed before administration of subsequent lines of therapy...
May 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28469968/the-selective-c-met-inhibitor-tepotinib-can-overcome-epidermal-growth-factor-receptor-inhibitor-resistance-mediated-by-aberrant-c-met-activation-in-nsclc-models
#3
Manja Friese-Hamim, Friedhelm Bladt, Giuseppe Locatelli, Uz Stammberger, Andree Blaukat
Non-small cell lung cancer (NSCLC) sensitive to first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often acquires resistance through secondary EGFR mutations, including the T790M mutation, aberrant c-Met receptor activity, or both. We assessed the ability of the highly selective c-Met inhibitor tepotinib to overcome EGFR TKI resistance in various xenograft models of NSCLC. In models with EGFR-activating mutations and low c-Met expression (patient explant-derived LU342, cell line PC-9), EGFR TKIs caused tumors to shrink, but growth resumed upon cessation of treatment...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28469919/osimertinib-administration-via-nasogastric-tube-in-an-egfr-t790m-positive-patient-with-leptomeningeal-metastases
#4
Takayuki Takeda, Hideki Itano, Mayumi Takeuchi, Yurika Nishimi, Masahiko Saitoh, Sorou Takeda
Patients with an epidermal growth factor receptor (EGFR) mutation are usually administered EGFR-tyrosine kinase inhibitors (TKIs) as standard-of-care treatment. However, acquired resistance occurs between 9 and 13 months. The T790M-resistant mutations are the most common, and osimertinib has been found to be effective in treating EGFR-T790M-positive patients. A 73-year-old female lung cancer patient with an EGFR-sensitizing mutation was receiving fourth-line chemotherapy when she complained of anorexia, headache, and irritability...
July 2017: Respirology Case Reports
https://www.readbyqxmd.com/read/28454365/downregulation-of-egfr-in-a-metastatic-brain-lesion-of-egfr-mutated-non-small-cell-lung-cancer-using-a-tyrosine-kinase-inhibitor-a-case-report
#5
Masatoshi Takagaki, Manabu Kinoshita, Kazumi Nishino, Masakazu Nakano, Hiroko Adachi, Morio Ueno, Masanori Kitamura, Yasunori Fujimoto, Kei Tashiro, Yasuhiko Tomita, Fumio Imamura, Toshiki Yoshimine
Brain metastasis is a common complication in patients with cancer, with lung cancer being the most frequent origin of brain metastases. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have begun to serve a pivotal role in lung cancer treatment and have been reported to demonstrate anticancer activity against brain metastases by penetrating the blood-brain barrier. The present study reports, to the best of our knowledge, the first case of EGFR-mutated non-small cell lung cancer (NSCLC) brain metastasis that was surgically resected while the lesion was responding to the EGFR-TKI erlotinib...
April 2017: Oncology Letters
https://www.readbyqxmd.com/read/28408243/erlotinib-and-bevacizumab-in-patients-with-advanced-non-small-cell-lung-cancer-and-activating-egfr-mutations-belief-an-international-multicentre-single-arm-phase-2-trial
#6
Rafael Rosell, Urania Dafni, Enriqueta Felip, Alessandra Curioni-Fontecedro, Oliver Gautschi, Solange Peters, Bartomeu Massutí, Ramon Palmero, Santiago Ponce Aix, Enric Carcereny, Martin Früh, Miklos Pless, Sanjay Popat, Athanasios Kotsakis, Sinead Cuffe, Paolo Bidoli, Adolfo Favaretto, Patrizia Froesch, Noemí Reguart, Javier Puente, Linda Coate, Fabrice Barlesi, Daniel Rauch, Michael Thomas, Carlos Camps, Jose Gómez-Codina, Margarita Majem, Rut Porta, Riyaz Shah, Emer Hanrahan, Roswitha Kammler, Barbara Ruepp, Manuela Rabaglio, Marie Kassapian, Niki Karachaliou, Rachel Tam, David S Shames, Miguel A Molina-Vila, Rolf A Stahel
BACKGROUND: The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation...
May 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28332047/mechanisms-of-resistance-to-target-therapies-in-non-small-cell-lung-cancer
#7
Francesco Facchinetti, Claudia Proto, Roberta Minari, Marina Garassino, Marcello Tiseo
Targeted therapies are revolutionizing the treatment of advanced non-small cell lung cancer (NSCLC). The discovery of key oncogenic events mainly in lung adenocarcinoma, like EGFR mutations or ALK rearrangements, has changed the treatment landscape while improving the prognosis of lung cancer patients. Inevitably, virtually all patients initially treated with targeted therapies develop resistance because of the emergence of an insensitive cellular population, selected by pharmacologic pressure. Diverse mechanisms of resistance, in particular to EGFR, ALK and ROS1 tyrosine-kinase inhibitors (TKIs), have now been discovered and may be classified in three different groups: (1) alterations in the target (such as EGFR T790M and ALK or ROS1 mutations); (2) activation of alternative pathways (i...
March 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28331001/quantitative-tyrosine-phosphoproteomics-of-epidermal-growth-factor-receptor-egfr-tyrosine-kinase-inhibitor-treated-lung-adenocarcinoma-cells-reveals-potential-novel-biomarkers-of-therapeutic-response
#8
Xu Zhang, Tapan Maity, Manoj K Kashyap, Mukesh Bansal, Abhilash Venugopalan, Sahib Singh, Shivangi Awasthi, Arivusudar Marimuthu, Harrys Kishore Charles Jacob, Natalya Belkina, Stephanie Pitts, Constance M Cultraro, Shaojian Gao, Guldal Kirkali, Romi Biswas, Raghothama Chaerkady, Andrea Califano, Akhilesh Pandey, Udayan Guha
Mutations in the Epidermal growth factor receptor (EGFR) kinase domain, such as the L858R missense mutation and deletions spanning the conserved sequence (747)LREA(750), are sensitive to tyrosine kinase inhibitors (TKIs). The gatekeeper site residue mutation, T790M accounts for around 60% of acquired resistance to EGFR TKIs. The first generation EGFR TKIs, erlotinib and gefitinib, and the second generation inhibitor, afatinib are FDA approved for initial treatment of EGFR mutated lung adenocarcinoma. The predominant biomarker of EGFR TKI responsiveness is the presence of EGFR TKI-sensitizing mutations...
May 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28274743/tolerable-and-effective-combination-of-full-dose-crizotinib-and-osimertinib-targeting-met-amplification-sequentially-emerging-after-t790m-positivity-in-egfr-mutant-non-small-cell-lung-cancer
#9
Emily R York, Marileila Varella-Garcia, Tami J Bang, Dara L Aisner, D Ross Camidge
No abstract text is available yet for this article.
March 6, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28271038/successful-crizotinib-monotherapy-in-egfr-mutant-lung-adenocarcinoma-with-acquired-met-amplification-after-erlotinib-therapy
#10
Katsuhiro Yoshimura, Naoki Inui, Masato Karayama, Yusuke Inoue, Noriyuki Enomoto, Tomoyuki Fujisawa, Yutaro Nakamura, Kengo Takeuchi, Haruhiko Sugimura, Takafumi Suda
MET is a driver oncogene in non-small-cell lung cancer (NSCLC), and its amplification is associated with acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. A 56-year-old Japanese male with lung adenocarcinoma harboring an EGFR exon 21 L858R mutation received erlotinib to which he responded for 12 months. After disease progression, re-biopsy analyses revealed newly developed MET amplification. Neither EGFR exon 20 T790M mutation nor MET exon 14 mutations were detected...
2017: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/28245967/pulsatile-erlotinib-in-egfr-positive-non-small-cell-lung-cancer-patients-with-leptomeningeal-and-brain-metastases-review%C3%A2-of%C3%A2-the-literature
#11
REVIEW
Joan How, Janelle Mann, Andrew N Laczniak, Maria Q Baggstrom
Patients with epidermal growth factor receptor (EGFR)-positive (EGFR(+)) non-small-cell lung cancer (NSCLC) show improved response rates when treated with tyrosine kinase inhibitors (TKIs) such as erlotinib. However, standard daily dosing of erlotinib often does not reach therapeutic concentrations within the cerebrospinal fluid (CSF), resulting in progression of central nervous system (CNS) disease. Intermittent, high-dose administration of erlotinib reaches therapeutic concentrations within the CSF and is well tolerated in patients...
February 9, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28230005/current-mechanism-of-acquired-resistance-to-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-and-updated-therapy-strategies-in-human-nonsmall-cell-lung-cancer
#12
REVIEW
Kaixian Zhang, Qianqian Yuan
Lung cancer continues to be a major health problem and the most common cancer-related mortality worldwide with about 80%-85% patients suffering from nonsmall cell lung cancer (NSCLC). More than 80% of NSCLC cases are often diagnosed as advanced stage and harbor epidermal growth factor receptor (EGFR) activating mutation. Although great success in initial response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are found in EGFR-mutant NSCLC patients, acquired resistance usually occurs on the continuous treatment...
December 2016: Journal of Cancer Research and Therapeutics
https://www.readbyqxmd.com/read/28219202/-precision-treatment-after-resistance-to-first-generation-egfr-tki-in-patients-with-non-small-cell-lung-cancer
#13
C Pi, Y C Zhang, C R Xu, Q Zhou
Recently, with the research progress in molecular classification, the treatment of advanced non-small cell lung cancer (NSCLC) has been established as a model of anti-tumor treatment of precision medicine. The discovery of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) has transformed the treatment of NSCLC from platinum based doublet chemotherapy into era of target therapy. EGFR-TKI, such as erlotinib and gefitinib, have been recommended as standard first-line treatment of patients with EGFR mutation...
February 23, 2017: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/28193529/heterogeneity-in-immune-marker-expression-after-acquisition-of-resistance-to-egfr-kinase-inhibitors-analysis-of-a-case-with-small-cell-lung-cancer-transformation
#14
Kenichi Suda, Isao Murakami, Hui Yu, Jihye Kim, Kim Ellison, Christopher J Rivard, Tetsuya Mitsudomi, Fred R Hirsch
INTRODUCTION: Expression of immune-markers is of scientific interest due to their potential roles as predictive biomarkers for immunotherapy. Although the microenvironment of metastatic tumors and/or therapy-inducible histological transformation may affect the expression of these immune-markers, there is little data regarding this context. METHODS: A 76-year-old never-smoking female with epidermal growth factor receptor (EGFR) mutated lung adenocarcinoma (AC) acquired resistance to gefitinib...
February 10, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28188446/treatment-options-for-egfr-t790m-negative-egfr-tyrosine-kinase-inhibitor-resistant-non-small-cell-lung-cancer
#15
Salvatore Corallo, Ettore D'Argento, Antonia Strippoli, Michele Basso, Santa Monterisi, Sabrina Rossi, Alessandra Cassano, Carlo M Barone
The introduction of first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib and afatinib) for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC) has dramatically improved patients' prognosis and quality of life (QoL). Unfortunately, after an initial and sometimes durable benefit from EGFR-TKI therapy, all patients with EGFR-mutant lung cancer eventually become resistant to the treatment and experience disease progression. In approximately 50% of these patients, genomic alterations in the EGFR kinase domain resulting in the mutant T790M are responsible for the resistance and this has led to the development of novel EGFR inhibitors active against mutant-T790M EGFR...
February 10, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28178168/rapid-intracranial-response-to-osimertinib-without-radiotherapy-in-nonsmall-cell-lung-cancer-patients-harboring-the-egfr-t790m-mutation-two-case-reports
#16
Taro Koba, Takashi Kijima, Takayuki Takimoto, Haruhiko Hirata, Yujiro Naito, Masanari Hamaguchi, Tomoyuki Otsuka, Muneyoshi Kuroyama, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Atsushi Kumanogoh
RATIONALE: Most of nonsmall cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations eventually acquire resistance to the first EGFR-tyrosine kinase inhibitors (TKIs) therapy after varying periods of treatment. Of note, approximately one-third of those patients develop brain metastases, which deteriorate their quality of life and survival. The effect of systemic chemotherapy on brain metastases after acquisition of EGFR-TKI resistance is limited, and thus far, whole-brain radiation therapy, which may cause the harmful effect on neurocognitive functions, has been the only established therapeutic option for especially symptomatic brain metastases...
February 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28159915/strategies-to-overcome-bypass-mechanisms-mediating-clinical-resistance-to-egfr-tyrosine-kinase-inhibition-in-lung-cancer
#17
REVIEW
Hatim Husain, Michael Scur, Ayesha Murtuza, Nam Bui, Brian Woodward, Razelle Kurzrock
The vast majority of patients with metastatic lung cancers who initially benefit from EGFR-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the challenge of treating tumors resistant to EGFR inhibitors. Resistance mechanisms include new, second-site mutations within EGFR (e.g., T790M and C797S), upregulation of MET kinase, upregulation of insulin growth factor receptor (IGFR), HER2 amplification, increased expression of AXL, BIM modulation, NF-κB activation, histologic switch to small-cell cancer, epithelial-to-mesenchymal transition, PDL1 expression with subsequent immune tolerance, and release of cytokines such as TGFβ and IL6...
February 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28149764/third-generation-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-in-t790m-positive-non-small-cell-lung-cancer-review-on-emerged-mechanisms-of-resistance
#18
REVIEW
Roberta Minari, Paola Bordi, Marcello Tiseo
Osimertinib, third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved in the US and EU for the treatment of EGFR mutant T790M-positive non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs, such as gefitinib, erlotinib and afatinib. Although exciting survival data and response rates have been registered in patients treated with this and other third-generation EGFR-TKIs, unfortunately acquired resistance still occurs after approximately 10 months...
December 2016: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/28141869/met-egfr-dimerization-in-lung-adenocarcinoma-is-dependent-on-egfr-mtations-and-altered-by-met-kinase-inhibition
#19
Elena Ortiz-Zapater, Richard W Lee, William Owen, Gregory Weitsman, Gilbert Fruhwirth, Robert G Dunn, Michael J Neat, Frank McCaughan, Peter Parker, Tony Ng, George Santis
Advanced lung cancer has poor survival with few therapies. EGFR tyrosine kinase inhibitors (TKIs) have high response rates in patients with activating EGFR mutations, but acquired resistance is inevitable. Acquisition of the EGFR T790M mutation causes over 50% of resistance; MET amplification is also common. Preclinical data suggest synergy between MET and EGFR inhibitors. We hypothesized that EGFR-MET dimerization determines response to MET inhibition, depending on EGFR mutation status, independently of MET copy number...
2017: PloS One
https://www.readbyqxmd.com/read/28138027/met-copy-number-gain-is-associated-with-gefitinib-resistance-in-leptomeningeal-carcinomatosis-of-egfr-mutant-lung-cancer
#20
Shigeki Nanjo, Sachiko Arai, Wei Wang, Shinji Takeuchi, Tadaaki Yamada, Akito Hata, Nobuyuki Katakami, Yasunori Okada, Seiji Yano
Leptomeningeal carcinomatosis (LMC) occurs frequently in EGFR-mutant lung cancer, and develops acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aimed to clarify the mechanism of EGFR-TKI resistance in LMC and seek for a novel therapeutic strategy. We examined EGFR mutations, including the T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 LMC and 20 extracranial lesions of EGFR-mutant lung cancer patients who became refractory to EGFR-TKI treatment. All the 32 specimens had the same baseline EGFR mutations, but the T790M mutation was less frequent in LMC specimens than in extracranial specimens (8% vs...
January 30, 2017: Molecular Cancer Therapeutics
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