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https://www.readbyqxmd.com/read/27843631/unravelling-signal-escape-through-maintained-egfr-activation-in-advanced-non-small-cell-lung-cancer-nsclc-new-treatment-options
#1
REVIEW
Jordi Remon, Benjamin Besse
The discovery of activating epidermal growth factor receptor (EGFR) mutations has opened up a new era in the development of more effective treatments for patients with non-small cell lung cancer (NSCLC). However, patients with EGFR-activating mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) ultimately develop acquired resistance (AR). Among known cases of patients with AR, 70% of the mechanisms involved in the development of AR to EGFR TKI have been identified and may be categorised as either secondary EGFR mutations such as the T790M mutation, activation of bypass track signalling pathways such as MET amplification, or histologic transformation...
2016: ESMO Open
https://www.readbyqxmd.com/read/27843613/mechanisms-of-resistance-to-egfr-targeted-drugs-lung-cancer
#2
REVIEW
Floriana Morgillo, Carminia Maria Della Corte, Morena Fasano, Fortunato Ciardiello
Despite the improvement in clinical outcomes derived by the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumours harbour EGFR-activating mutations, prognosis remains unfavourable because of the occurrence of either intrinsic or acquired resistance. We reviewed the published literature and abstracts of oral and poster presentations from international conferences addressing EGFR-TKIs resistance mechanisms discovered in preclinical models and in patients with NSCLC...
2016: ESMO Open
https://www.readbyqxmd.com/read/27821131/frequency-of-egfr-t790m-mutation-and-multimutational-profiles-of-rebiopsy-samples-from-non-small-cell-lung-cancer-developing-acquired-resistance-to-egfr-tyrosine-kinase-inhibitors-in-japanese-patients
#3
Ryo Ko, Hirotsugu Kenmotsu, Masakuni Serizawa, Yasuhiro Koh, Kazushige Wakuda, Akira Ono, Tetsuhiko Taira, Tateaki Naito, Haruyasu Murakami, Mitsuhiro Isaka, Masahiro Endo, Takashi Nakajima, Yasuhisa Ohde, Nobuyuki Yamamoto, Kazuhisa Takahashi, Toshiaki Takahashi
BACKGROUND: The majority of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation eventually develop resistance to EGFR tyrosine kinase inhibitors (TKIs). Minimal information exists regarding genetic alterations in rebiopsy samples from Asian NSCLC patients who develop acquired resistance to EGFR-TKIs. METHODS: We retrospectively reviewed the medical records of patients with NSCLC harboring EGFR mutations who had undergone rebiopsies after developing acquired resistance to EGFR-TKIs...
November 8, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27770386/mechanisms-of-resistance-to-third-generation-egfr-tyrosine-kinase-inhibitors
#4
Shuhang Wang, Yongping Song, Feifei Yan, Delong Liu
The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9-13 months of therapy...
October 21, 2016: Frontiers of Medicine
https://www.readbyqxmd.com/read/27747151/a-long-term-survivor-of-non-small-cell-lung-cancer-harboring-concomitant-egfr-mutation-and-alk-translocation
#5
Fumio Imamura, Takako Inoue, Madoka Kimura, Kazumi Nishino, Toru Kumagai
In January 2003, a 55-year old, non-smoking woman visited our hospital to undergo treatment for T4N0M0 pulmonary adenocarcinoma of the left lung. Until death in October 2015, she received over 20 lines of treatment including a second line therapy with gefitinib, which showed long response. In March 2014, she noticed the left axillar lymph node swelling. Aspiration cytology of the lymph node revealed the presence of adenocarcinoma harboring EGFR exon 19 deletion (Ex19del) but not T790M. Concomitant ALK translocation of variant 1 was also detected...
2016: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/27726115/early-18-f-fdg-uptake-as-a-reliable-imaging-biomarker-of-t790m-mediated-resistance-but-not-met-amplification-in-non-small-cell-lung-cancer-treated-with-egfr-tyrosine-kinase-inhibitors
#6
Viviana De Rosa, Francesca Iommelli, Marcello Monti, Ciro Gabriele Mainolfi, Rosa Fonti, Silvana Del Vecchio
BACKGROUND: The two main mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) are the occurrence of T790M secondary mutation in the kinase domain of EGFR and MET amplification. The aim of the present study was to test whether early changes of (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in animal models bearing erlotinib-resistant NSCLC may have different imaging patterns of response to erlotinib depending on the molecular mechanisms underlying resistance...
December 2016: EJNMMI Research
https://www.readbyqxmd.com/read/27717507/egfr-as-a-pharmacological-target-in-egfr-mutant-non-small-cell-lung-cancer-where-do-we-stand-now
#7
E-E Ke, Yi-Long Wu
Targeting the epidermal growth factor receptor (EGFR) using tyrosine kinase inhibitors (TKIs) is highly effective in terms of tumor response rate, survival, and quality of life. However, acquired resistance to EGFR-TKIs is inevitable. Ongoing clinical trials will provide evidence for optimal strategies for patients with EGFR mutant non-small-cell lung cancer (NSCLC) in the near future. Numerous new agents are specifically addressing resistance mechanisms; mature data are related to the T790M mutation and MET pathway activation...
November 2016: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/27612490/acquired-resistance-mechanisms-to-combination-met-tki-egfr-tki-exposure-in-met-amplified-egfr-tki-resistant-lung-adenocarcinoma-harboring-an-activating-egfr-mutation
#8
Toshimitsu Yamaoka, Tohru Ohmori, Motoi Ohba, Satoru Arata, Yasunari Kishino, Yasunori Murata, Sojiro Kusumoto, Hiroo Ishida, Takao Shirai, Takashi Hirose, Tsukasa Ohnishi, Yasutsuna Sasaki
Met-amplified epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation is responsive to concurrent EGFR-TKI and Met-TKI treatment in a preclinical model. Here, we determined that Met-amplified gefitinib-resistant cells acquire dual resistance to inhibition of EGFR and Met tyrosine kinase activities. PC-9 lung adenocarcinoma cells harboring 15-bp deletions (Del E746_A750) in EGFR exon 19 were treated with increasing concentrations of the Met-TKI PHA665752 and 1 μM gefitinib for 1 year; three resistant clones were established via Met amplification...
September 9, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27528220/mutational-profiling-of-non-small-cell-lung-cancer-patients-resistant-to-first-generation-egfr-tyrosine-kinase-inhibitors-using-next-generation-sequencing
#9
Ying Jin, Yang Shao, Xun Shi, Guangyuan Lou, Yiping Zhang, Xue Wu, Xiaoling Tong, Xinmin Yu
Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is secondary EGFR-T790M mutation. Other mechanisms, such as HER2 and MET amplifications, and PIK3CA mutations, were also reported...
August 12, 2016: Oncotarget
https://www.readbyqxmd.com/read/27486808/rapid-intracranial-response-to-osimertinib-in-a-patient-with-epidermal-growth-factor-receptor-t790m-positive-adenocarcinoma-of-the-lung
#10
Hermann Reichegger, Wolfram Jochum, Diana Förbs, Claudia Hader, Martin Früh
BACKGROUND: Osimertinib (AZD9291, Tagrisso) is a potent, irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). CASE REPORT: Our report demonstrates that osimertinib is able to inhibit the growth of a radiotherapy- and surgery-refractory EGFR T790M-positive brain metastasis in a patient with lung adenocarcinoma. CONCLUSION: These data show that re-biopsy in EGFR-mutated non-small cell lung cancer patients with acquired TKI resistance should be performed...
2016: Oncology Research and Treatment
https://www.readbyqxmd.com/read/27468937/a-highly-sensitive-and-quantitative-test-platform-for-detection-of-nsclc-egfr-mutations-in-urine-and-plasma
#11
Karen L Reckamp, Vladislava O Melnikova, Chris Karlovich, Lecia V Sequist, D Ross Camidge, Heather Wakelee, Maurice Perol, Geoffrey R Oxnard, Karena Kosco, Peter Croucher, Errin Samuelsz, Cecile Rose Vibat, Shiloh Guerrero, Jennifer Geis, David Berz, Elaina Mann, Shannon Matheny, Lindsey Rolfe, Mitch Raponi, Mark G Erlander, Shirish Gadgeel
INTRODUCTION: In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible. METHODS: Short footprint mutation enrichment next-generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of rociletinib in previously treated patients with EGFR mutant-positive advanced NSCLC...
October 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27450722/met-gene-amplification-and-protein-hyperactivation-is-a-mechanism-of-resistance-to-both-first-and-third-generation-egfr-inhibitors-in-lung-cancer-treatment
#12
Puyu Shi, You-Take Oh, Guojing Zhang, Weilong Yao, Ping Yue, Yikun Li, Rajani Kanteti, Jacob Riehm, Ravi Salgia, Taofeek K Owonikoko, Suresh S Ramalingam, Mingwei Chen, Shi-Yong Sun
The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs; e.g., AZD9291), which selectively and irreversibly inhibit EGFR activating and T790M mutants, represent very promising therapeutic options for patients with non-small cell lung cancer (NSCLC) that has become resistant to 1st generation EGFR-TKIs due to T790M mutation. However, eventual resistance to the 3rd generation EGFR-TKIs has already been described in the clinic, resulting in disease progression. Therefore, there is a great challenge and urgent need to understand how this resistance occurs and to develop effective strategies to delay or overcome the resistance...
October 1, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27393507/high-met-amplification-level-as-a-resistance-mechanism-to-osimertinib-azd9291-in-a-patient-that-symptomatically-responded-to-crizotinib-treatment-post-osimertinib-progression
#13
Sai-Hong Ignatius Ou, Nikita Agarwal, Siraj M Ali
Third-generation EGFR TKI has been approved in the US and EU for the treatment of EGFR mutant T790M+ NSCLC patients that are resistant to first- or second generation EGFR TKIs. Here we report a patient who developed resistance to osimertinib after a confirmed partial response for 9 months. Pre-osimertinib and post-osimertinib tumor biopsy revealed the emergence of high level of MET amplification (30 copies) post osimertinib treatment. Patient was treated with single agent crizotinib, a known MET inhibitor, with transient symptomatic benefit...
August 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27393503/temporal-changes-of-egfr-mutations-and-t790m-levels-in-tumour-and-plasma-dna-following-azd9291-treatment
#14
Puey Ling Chia, Hongdo Do, Adrienne Morey, Paul Mitchell, Alexander Dobrovic, Thomas John
AZD9291, a T790M specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has demonstrated impressive response rates in tumours harbouring the EGFR T790M resistance mutation. Emergence of resistance to AZD9291 has been shown to occur through several different mechanisms including the development of new mutations (e.g. C797S) in the EGFR tyrosine kinase domain. We studied two patients with paired tumour biopsies and blood samples pre- and post-progression on AZD9291 to explore possible resistance mechanisms...
August 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27283993/circulating-tumour-dna-profiling-reveals-heterogeneity-of-egfr-inhibitor-resistance-mechanisms-in-lung-cancer-patients
#15
Jacob J Chabon, Andrew D Simmons, Alexander F Lovejoy, Mohammad S Esfahani, Aaron M Newman, Henry J Haringsma, David M Kurtz, Henning Stehr, Florian Scherer, Chris A Karlovich, Thomas C Harding, Kathleen A Durkin, Gregory A Otterson, W Thomas Purcell, D Ross Camidge, Jonathan W Goldman, Lecia V Sequist, Zofia Piotrowska, Heather A Wakelee, Joel W Neal, Ash A Alizadeh, Maximilian Diehn
Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1...
June 10, 2016: Nature Communications
https://www.readbyqxmd.com/read/27281561/a-prospective-evaluation-of-circulating-tumor-cells-and-cell-free-dna-in-egfr-mutant-non-small-cell-lung-cancer-patients-treated-with-erlotinib-on-a-phase-ii-trial
#16
Masahiko Yanagita, Amanda J Redig, Cloud P Paweletz, Suzanne E Dahlberg, Allison O'Connell, Nora Feeney, Myriam Taibi, David Boucher, Geoffrey R Oxnard, Bruce E Johnson, Daniel B Costa, David M Jackman, Pasi A Jänne
BACKGROUND: Genotype-directed therapy is standard-of-care for advanced NSCLC, but obtaining tumor tissue for genotyping remains a challenge. CTC or cfDNA analysis may allow for noninvasive evaluation. This prospective trial evaluated CTCs and cfDNA in EGFR-mutant NSCLC patients treated with erlotinib until progression. METHODS: EGFR-mutant NSCLC patients were enrolled in a phase II trial of erlotinib. Blood was collected at baseline, every 2 months on study, and at disease progression...
June 8, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27259997/the-coexistence-of-met-over-expression-and-an-egfr-t790m-mutation-is-related-to-acquired-resistance-to-egfr-tyrosine-kinase-inhibitors-in-advanced-non-small-cell-lung-cancer
#17
Lan-Ying Gou, An-Na Li, Jin-Ji Yang, Xu-Chao Zhang, Jian Su, Hong-Hong Yan, Zhi Xie, Na-Na Lou, Si-Yang Liu, Zhong-Yi Dong, Hong-Fei Gao, Qing Zhou, Wen-Zhao Zhong, Chong-Rui Xu, Yi-Long Wu
MET overexpression and the EGFR T790M mutation are both associated with acquired resistance (AR) to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC). We characterized the frequency, underlying molecular mechanisms, and subsequent treatment for AR in MET overexpressing NSCLC patients with or without the T790M mutation. The study participants were 207 patients with advanced NSCLC and AR to EGFR-TKIs. The percentages of MET-, T790M- and MET/T790M-positive patients were 20...
May 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/27180141/circulating-cell-free-nucleic-acids-and-platelets-as-a-liquid-biopsy-in-the-provision-of-personalized-therapy-for-lung-cancer-patients
#18
L Sorber, K Zwaenepoel, V Deschoolmeester, P E Y Van Schil, J Van Meerbeeck, F Lardon, C Rolfo, P Pauwels
Lung cancer is the predominant cause of cancer-related mortality in the world. The majority of patients present with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Treatment for NSCLC is evolving from the use of cytotoxic chemotherapy to personalized treatment based on molecular alterations. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of circulating cell-free nucleic acids (cfNA), consisting of both circulating cell-free (tumoral) DNA (cfDNA-ctDNA) and RNA (cfRNA), as a liquid biopsy in lung cancer...
May 4, 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27033384/-mutation-status-of-epidermal-growth-factor-receptor-and-kras-gene-in-non-small-cell-lung-cancers-at-xuanwei-regions-of-yunnan-province
#19
C S Yang, X Y Pan, Q Feng, Y Y Wang, W M Xu, T Jiang, L Wang, J L Yang, L Wang
OBJECTIVE: To investigate the mutation status of epidermal growth factor receptor (EGFR) and KRAS gene in patients with non-small cell lung cancer (NSCLC) in Xuanwei, Yunnan and to correlate the mutation status with clinicopathologic features. METHODS: Mutation status of exons 18, 19, 20 and 21 of EGFR, and codons 12, 13 of KRAS in 63 cases of NSCLC were analyzed by gene sequencing and ARMS-Taqman probe method. Correlation with patients' clinicopathological characteristics was performed...
April 8, 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/27010480/molecular-dynamics-analysis-of-binding-of-kinase-inhibitors-to-wt-egfr-and-the-t790m-mutant
#20
Jiyong Park, Joseph J McDonald, Russell C Petter, K N Houk
Epidermal growth factor receptor (EGFR) inhibitors interrupt EGFR-dependent cellular signaling pathways that lead to accelerated tumor growth and proliferation. Mutation of a threonine in the inhibitor binding pocket, known as the "gatekeeper", to methionine (T790M) confers acquired resistance to several EGFR-selective inhibitors. We studied interactions between EGFR inhibitors and the gatekeeper residues of the target protein. Thermodynamic integration (TI) with Amber14 indicates that the binding energies of gefitinib and AEE788 to the active state of the T790M mutant EGFR is 3 kcal/mol higher than to the wild type (WT), whereas ATP binding energy to the mutant is similar to the WT...
April 12, 2016: Journal of Chemical Theory and Computation
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