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https://www.readbyqxmd.com/read/28436422/rational-design-of-non-resistant-targeted-cancer-therapies
#1
Francisco Martínez-Jiménez, John P Overington, Bissan Al-Lazikani, Marc A Marti-Renom
Drug resistance is one of the major problems in targeted cancer therapy. A major cause of resistance is changes in the amino acids that form the drug-target binding site. Despite of the numerous efforts made to individually understand and overcome these mutations, there is a lack of comprehensive analysis of the mutational landscape that can prospectively estimate drug-resistance mutations. Here we describe and computationally validate a framework that combines the cancer-specific likelihood with the resistance impact to enable the detection of single point mutations with the highest chance to be responsible of resistance to a particular targeted cancer therapy...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28435529/-18-f-labeled-pyrido-3-4-d-pyrimidine-as-an-effective-probe-for-imaging-of-l858r-mutant-epidermal-growth-factor-receptor
#2
Hiroyuki Kimura, Haruka Okuda, Masumi Ishiguro, Kenji Arimitsu, Akira Makino, Ryuichi Nishii, Anna Miyazaki, Yusuke Yagi, Hiroyuki Watanabe, Ikuo Kawasaki, Masahiro Ono, Hideo Saji
In nonsmall-cell lung carcinoma patients, L858R mutation of epidermal growth factor receptor (EGFR) is often found, and molecular target therapy using EGFR tyrosine kinase inhibitors is effective for the patients. However, the treatment frequently develops drug resistance by secondary mutation, of which approximately 50% is T790M mutation. Therefore, the ability to predict whether EGFR will undergo secondary mutation is extremely important. We synthesized a novel radiofluorinated 4-(anilino)pyrido[3,4-d]pyrimidine derivative ([(18)F]APP-1) and evaluated its potential as a positron emission tomography (PET) imaging probe to discriminate the difference in mutations of tumors...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28433077/development-and-clinical-utility-of-a-blood-based-test-service-for-the-rapid-identification-of-actionable-mutations-in-non-small-cell-lung-carcinoma
#3
Hestia Mellert, Trudi Foreman, Leisa Jackson, Dianna Maar, Scott Thurston, Kristina Koch, Amanda Weaver, Samantha Cooper, Nicholas Dupuis, Ubaradka G Sathyanarayana, Jakkie Greer, Westen Hahn, Dawne Shelton, Paula Stonemetz, Gary A Pestano
Nearly 80% of cancer patients do not have genetic mutation results available at initial oncology consultation; up to 25% of patients begin treatment before receiving their results. These factors hinder the ability to pursue optimal treatment strategies. This study validates a blood-based genome-testing service that provides accurate results within 72 hours. We focused on targetable variants in advanced non-small cell lung carcinoma-epidermal growth factor receptor gene (EGFR) variant L858R, exon 19 deletion (ΔE746-A750), and T790M; GTPase Kirsten ras gene (KRAS) variants G12C/D/V; and echinoderm microtubule associated protein like and 4 anaplastic lymphoma receptor tyrosine kinase fusion (EML4-ALK) transcripts 1/2/3...
May 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28432840/detection-of-egfr-mutations-in-patients-with-non-small-cell-lung-cancer-by-high-resolution-melting-comparison-with-other-methods
#4
Carlos Martínez-Carretero, Fernando Iguaz Pascual, Antonio Rus, Ivan Bernardo
BACKGROUND: The discovery of mutations in the epidermal growth factor receptor gene (EGFR) related to the clinical response to tyrosine kinase inhibitors, has transformed the management of non-small cell lung cancer (NSCLC). Several methods have been developed for determination of mutations in EGFR, with different sensitivity and potential ability to detect a different number of mutations. METHODS: We developed a screening method by high resolution melting (HRM) to detect EGFR mutations, and compared the results of 123 fixed in formalin and paraffin embedded (FFPE) tumor tissue samples with the detection of mutations by allele-specific PCR...
April 22, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/28428148/plasma-ctdna-analysis-for-detection-of-the-egfr-t790m-mutation-in-patients-with-advanced-non-small-cell-lung-cancer
#5
Suzanne Jenkins, James C-H Yang, Suresh S Ramalingam, Karen Yu, Sabina Patel, Susie Weston, Rachel Hodge, Mireille Cantarini, Pasi A Jänne, Tetsuya Mitsudomi, Glenwood D Goss
INTRODUCTION: Tumor biopsies for detecting epidermal growth factor receptor mutations (EGFRm) in advanced non-small cell lung cancer (NSCLC) are invasive, costly and not always feasible for patients with late-stage disease. The clinical utility of the cobas(®) EGFR Mutation Test v2 with plasma samples from patients with NSCLC at disease progression following previous EGFR-tyrosine kinase inhibitor (TKI) therapy was investigated to determine osimertinib treatment eligibility. METHODS: Matched tumor tissue and plasma samples from patients screened for AURA extension and AURA2 phase II studies were tested for EGFRm using tissue- and plasma-based cobas(®) EGFR Mutation Tests v2...
April 17, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28426996/design-synthesis-sar-discussion-in%C3%A2-vitro-and-in%C3%A2-vivo-evaluation-of-novel-selective-egfr-modulator-to-inhibit-l858r-t790m-double-mutants
#6
Haoyang Zhang, Wenkui Wu, Chao Feng, Zhaogang Liu, Enhe Bai, Xueyuan Wang, Meng Lei, Hao Cheng, Huayun Feng, Jingmiao Shi, Jia Wang, Zhao Zhang, Tao Jin, Shanshan Chen, Shihe Hu, Yongqiang Zhu
Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model...
April 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28423705/addition-of-bevacizumab-for-malignant-pleural-effusion-as-the-manifestation-of-acquired-egfr-tki-resistance-in-nsclc-patients
#7
Tao Jiang, Aiwu Li, Chunxia Su, Xuefei Li, Chao Zhao, Shengxiang Ren, Caicun Zhou, Jun Zhang
This study aimed to investigate the role of bevacizumab in patients with advanced non-small cell lung cancer (NSCLC) who had developed acquired resistance to EGFR-TKIs therapy that manifested as malignant pleural effusion (MPE). In total, 86 patients were included. 47 patients received bevacizumab plus continued EGFR-TKIs and 39 patients received bevacizumab plus chemotherapy. The curative efficacy rate for MPE in bevacizumab plus EGFR-TKIs group was significantly higher than that in bevacizumab plus chemotherapy group (89...
March 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422737/generation-of-lung-cancer-cell-lines-harboring-egfr-t790m-mutation-by-crispr-cas9-mediated-genome-editing
#8
Mi-Young Park, Min Hee Jung, Eun Young Eo, Seokjoong Kim, Sang Hoon Lee, Yeon Joo Lee, Jong Sun Park, Young Jae Cho, Jin Haeng Chung, Cheol Hyeon Kim, Ho Il Yoon, Jae Ho Lee, Choon-Taek Lee
Tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib are effective against lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) mutations. However, cancer cells can develop resistance to these agents with prolonged exposure; in over 50% of cases, this is attributable to the EGFR T790M mutation. Moreover, additional resistance mutations can arise with the use of new drugs. Cancer cell lines with specific mutations can enable the study of resistance mechanisms. In this study, we introduced the EGFR T790M mutation into the PC9 human lung cancer cell line-which has a deletion in exon 19 of the EGFR gene-by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas)9-mediated genome editing...
March 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28420725/monitoring-daily-dynamics-of-early-tumor-response-to-targeted-therapy-by-detecting-circulating-tumor-dna-in-urine
#9
Hatim Husain, Vladislava O Melnikova, Karena Kosco, Brian Woodward, Soham More, Sandeep C Pingle, Elizabeth Weihe, Ben Ho Park, Muneesh Tewari, Mark G Erlander, Ezra E W Cohen, Scott M Lippman, Razelle Kurzrock
Purpose: Non-invasive drug biomarkers for the early assessment of tumor response can enable adaptive therapeutic decision-making and proof-of-concept studies for investigational drugs. Circulating tumor DNA (ctDNA) is released into the circulation by tumor cell turnover and has been shown to be detectable in urine. Experimental Design : We tested the hypothesis that dynamic changes in epidermal growth factor receptor (EGFR) activating (exon 19del and L858R) and resistance (T790M) mutation levels detected in urine could inform tumor response within days of therapy for advanced non-small cell lung cancer (NSCLC) patients receiving osimertinib, a second line third generation anti-EGFR tyrosine kinase inhibitor...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28419328/efficacy-and-safety-of-osimertinib-in-a-japanese-compassionate-use-program
#10
Yutaka Fujiwara, Yasushi Goto, Shintaro Kanda, Hidehito Horinouchi, Noboru Yamamoto, Naomi Sakiyama, Reiko Ando Makihara, Yuichiro Ohe
Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the T790M mutation of EGFR. In 2016, AstraZeneca conducted a compassionate use program for osimertinib in Japan. Methods: Eighteen consecutive patients with histologically proven non-small-cell lung cancer (NSCLC) and harboring the T790M EGFR mutation participated in the compassionate use program between 1 April and 25 May 2016, at the National Cancer Center Hospital...
April 13, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28418848/the-prognostic-role-of-pretreatment-epidermal-growth-factor-receptor-t790m-mutation-in-advanced-non-small-cell-lung-cancer-patients-treated-with-egfr-tyrosine-kinase-inhibitors
#11
Guangzhi Ma, Jing Zhang, Liyuan Yin, Hai Jiang, Weiwei Zhang, Yanlin Song, Ming Liu
PURPOSE: The outcome of pretreatment epidermal growth factor receptor (EGFR) T790M mutation in EGFR mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) is controversial, this study aimed to evaluate the prognostic role of pretreatment T790M in advanced NSCLC patients treated with EGFR TKIs. RESULTS: A total of 7 eligible studies containing 179 cases and 281 controls were included in the meta-analysis. The pooled hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were 2...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416959/predictive-factors-for-switched-egfr-tki-retreatment-in-patients-with-egfr-mutant-non-small-cell-lung-cancer
#12
Byoung Soo Kwon, Ji Hyun Park, Woo Sung Kim, Joon Seon Song, Chang-Min Choi, Jin Kyung Rho, Jae Cheol Lee
BACKGROUND: Third-generation tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKIs) have proved efficacious in treating non-small cell lung cancer (NSCLC) patients with acquired resistance resulting from the T790M mutation. However, since almost 50% patients with the acquired resistance do not harbor the T790M mutation, retreatment with first- or second-generation EGFR-TKIs may be a more viable therapeutic option. Here, we identified positive response predictors to retreatment, in patients who switched to a different EGFR-TKI, following initial treatment failure...
April 2017: Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/28416737/efficacy-of-continuous-egfr-inhibition-and-role-of-hedgehog-in-egfr-acquired-resistance-in-human-lung-cancer-cells-with-activating-mutation-of-egfr
#13
Carminia Maria Della Corte, Umberto Malapelle, Elena Vigliar, Francesco Pepe, Giancarlo Troncone, Vincenza Ciaramella, Teresa Troiani, Erika Martinelli, Valentina Belli, Fortunato Ciardiello, Floriana Morgillo
PURPOSE: The aim of this work was to investigate the efficacy of sequential treatment with first-, second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the mechanisms of acquired resistance occurring during the sequential use of these inhibitors. EXPERIMENTAL DESIGN: We developed an in vivo model of acquired resistance to EGFR-inhibitors by treating nude mice xenografted with HCC827, a human non-small-cell lung cancer (NSCLC) cell line harboring EGFR activating mutation, with a sequence of first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) (erlotinib and gefitinib), of second-generation EGFR-TKI (afatinib) plus/minus the anti-EGFR monoclonal antibody cetuximab, and of third-generation EGFR-TKI (osimertinib)...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416483/sfk-fak-signaling-attenuates-osimertinib-efficacy-in-both-drug-sensitive-and-drug-resistant-models-of-egfr-mutant-lung-cancer
#14
Eiki Ichihara, David Westover, Catherine B Meador, Yingjun Yan, Joshua A Bauer, Pengcheng Lu, Fei Ye, Amanda Kulick, Elisa De Stanchina, Robert McEwen, Marc Ladanyi, Darren Cross, William Pao, Christine M Lovly
Mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of EGFR-mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with EGFR-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by development of acquired resistance...
April 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28414972/an-lc-ms-ms-method-for-quantification-of-ac0010-a-novel-mutant-selective-epidermal-growth-factor-receptor-egfr-inhibitor-and-its-metabolites-in-human-plasma-and-the-application-to-a-pharmacokinetic-study
#15
Lu Wang, Xin Zheng, Weicong Wang, Pei Hu, Ji Jiang
AC0010 is an irreversible, mutant-selective EGFR inhibitor that effectively inhibits EGFR active and T790M resistance mutations in non-small cell lung cancer (NSCLC). A sensitive ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) method was developed and fully validated for determining AC0010 and its metabolites in human plasma. The samples were purified by solid-phase extraction (SPE) columns and separated on a BEH C18 column. Electrospray ionization (ESI) in positive ion mode and multiple reaction monitoring (MRM) were used to monitor the ion transitions of AC0010 (m/z 488→257) and its metabolites M1 (m/z 474→403), M2 (m/z 504→487), M4 (m/z 434→377), M7 (m/z 490→405), MII-1 (m/z 651→434) and MII-2 (m/z 609→434)...
March 28, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28413660/dramatic-intracranial-response-to-osimertinib-in-a-poor-performance-status-patient-with-lung-adenocarcinoma-harboring-the-epidermal-growth-factor-receptor-t790m-mutation-a-case-report
#16
Takehiro Uemura, Tetsuya Oguri, Minami Okayama, Hiromi Furuta, Yoshihiro Kanemitsu, Osamu Takakuwa, Hirotsugu Ohkubo, Masaya Takemura, Ken Maeno, Yutaka Ito, Akio Niimi
We herein report a case of dramatic intracranial response to osimertinib in a poor performance status patient with lung adenocarcinoma harboring the epidermal growth factor receptor (EGFR) T790M mutation encoded in exon 20. The patient was a 59-year-old woman with EGFR exon 19 deletion-positive lung adenocarcinoma, who relapsed with multiple brain metastases. Computed tomography-guided biopsy of the left pleural tumor revealed adenocarcinoma harboring an EGFR exon 19 deletion and an EGFR T790M mutation encoded in exon 20...
April 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28408245/combined-bevacizumab-and-erlotinib-treatment-in-patients-with-lung-cancer-with-the-t790m-resistance-mutation
#17
Tetsuya Mitsudomi
No abstract text is available yet for this article.
April 10, 2017: Lancet Respiratory Medicine
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
#18
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...
April 10, 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28407693/discovery-and-characterization-of-a-novel-irreversible-egfr-mutants-selective-and-potent-kinase-inhibitor-chmfl-egfr-26-with-a-distinct-binding-mode
#19
Chen Hu, Aoli Wang, Hong Wu, Ziping Qi, Xixiang Li, Xiao-E Yan, Cheng Chen, Kailin Yu, Fengming Zou, Wenchao Wang, Wei Wang, Jiaxin Wu, Juan Liu, Beilei Wang, Li Wang, Tao Ren, Shanchun Zhang, Cai-Hong Yun, Jing Liu, Qingsong Liu
EGFR T790M mutation accounts for about 40-55% drug resistance for the first generation EGFR kinase inhibitors in the NSCLC. Starting from ibrutinib, a highly potent irreversible BTK kinase inhibitor, which was also found to be moderately active to EGFR T790M mutant, we discovered a highly potent irreversible EGFR inhibitor CHMFL-EGFR-26, which is selectively potent against EGFR mutants including L858R, del19, and L858R/T790M. It displayed proper selectivity window between the EGFR mutants and the wide-type...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28407039/tumor-immune-microenvironment-and-nivolumab-efficacy-in-egfr-mutation-positive-non-small-cell-lung-cancer-based-on-t790m-status-after-disease-progression-during-egfr-tki-treatment
#20
K Haratani, H Hayashi, T Tanaka, H Kaneda, Y Togashi, K Sakai, K Hayashi, S Tomida, Y Chiba, K Yonesaka, Y Nonagase, T Takahama, J Tanizaki, K Tanaka, T Yoshida, K Tanimura, M Takeda, H Yoshioka, T Ishida, T Mitsudomi, K Nishio, K Nakagawa
Background.: The efficacy of programmed death-1 (PD-1) blockade in epidermal growth factor receptor gene ( EGFR ) mutation-positive non-small cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR . Patients and Methods.: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A)...
April 12, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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