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Yang Chen, Youyou Wang, Lujun Zhao, Ping Wang, Jifeng Sun, Rudi Bao, Chenghai Li, Ningbo Liu
Objective: To investigate the potential of HS-10182, a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), as a radiosensitizer in non-small cell lung cancer (NSCLC). Methods: Two cell lines of NSCLCs, A549 that possesses wild-type (WT) EGFRs and H1975 that possesses EGFR L858R/T790M double mutations, were treated with HS-10182 at various concentrations, and cell viabilities were determined using the MTS assay. The cells were tested by clonogenic survival assays to identify the radiosensitivity of both groups...
February 2018: Cancer Biology & Medicine
Elena Castellanos-Rizaldos, Dominik G Grimm, Vasisht Tadigotla, James Hurley, John Healy, Patricia L Neal, Mia Sher, Raajdeep Venkatesan, Chris Karlovich, Mitch Raponi, Anne K Krug, Mikkel Noerholm, Jihane Tannous, Bakhos A Tannous, Luis E Raez, Johan Skog
PURPOSE: About 60% of non-small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a non-invasive option to detect the mutation, however sensitivity is low as many patients have too few detectable copies in circulation...
March 13, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Fusheng Zhou, Liang Zhang, Yunzhou Jin, Wei Liu, Pengfei Cheng, Xiangyu He, Jing Xie, Sida Shen, Jing Lei, Haixia Ji, Yi Hu, Yingtao Liu, Yumin Cui, Qiang Lv, Jiong Lan
A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the EGFR L858R/T790M. The most representative compound 28 showed high activity against EGFR L858R/T790M kinase (IC50  = 4 nM) and 22-fold selectivity against wild type EGFR. Moreover, compound 28 potently inhibited EGFR L858R/T790M phosphorylation (IC50  = 41 nM) and cellular proliferation (IC50  = 37 nM) in the H1975 cell line, while being significantly less toxic to A431 cells...
December 6, 2017: Bioorganic & Medicinal Chemistry Letters
Zhang Zhang, Jian Zou, Lei Yu, Jinfeng Luo, Yan Li, Zhengchao Tu, Xiaomei Ren, Hongcheng Wei, Liyan Song, Xiaoyun Lu, Ke Ding
YL143 was identified as a novel wild-type sparing EGFRT790M inhibitor with good pharmacokinetic properties. It potently suppresses EGFRL858R/T790M with an 50% inhibitory concentration (IC50 ) value of 2.0 ± 0.3 nmol/L, but is approximately 92-folds less potent against EGFRWT kinase. YL143 suppresses cellular proliferation and induces G0/G1 phase arrest and apoptosis in H1975 cells with EGFRL858R/T790M mutation at 30 nmol/L. It also exhibits acceptable pharmacokinetics (PK) parameters with an oral bioavailability value of 25...
March 13, 2018: Cancer Medicine
Helena Yu, Ken Suzawa, Emmet J Jordan, Ahmet Zehir, Andy Ni, Hyunjae Ryan Kim, Mark G Kris, Matthew D Hellmann, Bob T Li, Romel Somwar, David B Solit, Michael F Berger, Maria E Arcila, Gregory J Riely, Marc Ladanyi
PURPOSE: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.      Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR mutant lung cancer. Clinical data were collected and correlated with somatic mutation data...
March 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Carminia Maria Della Corte, Vincenza Ciaramella, Claudia Cardone, Silvia La Monica, Roberta Alfieri, Pier Giorgio Petronini, Umberto Malapelle, Elena Vigliar, Francesco Pepe, Giancarlo Troncone, Maria Domenica Castellone, Teresa Troiani, Erika Martinelli, Fortunato Ciardiello, Floriana Morgillo
HYPOTHESIS: Osimertinib showed great clinical efficacy for activated-EGFR-NSCLC patients treatment. The aim of this work was to test the efficacy of a complete EGFR-inhibition by osimertinib plus the monoclonal antibody, cetuximab, or the MEK1/2-inhibitor, selumetinib, in EGFR-mutated-NSCLC in vivo models. METHODS: We evaluated combinations of osimertinib plus selumetinib/cetuximab in HCC827 (E746-A759del/T790M-), H1975 (L858R/T790M+) and PC9-T790M (E746-A759del /T790M+) xenografts, in second-line after the developing of resistance to osimertinib and in first-line, and we explored mechanisms of resistance to these treatments...
March 8, 2018: Journal of Thoracic Oncology
Lianfang Ni, Ligong Nie
Targeted therapy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) has been the standard modality as first-line treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-TKIs has been approved to overcome the EGFR T790M mutation in patients resistant to the first-or second-generation TKIs, which brings more survival benefits for patients with advanced NSCLC. Unfortunately, acquired resistance inevitably develops after application of approximately 10 months...
February 20, 2018: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Weihua Li, Tian Qiu, Lei Guo, Yun Ling, Yibo Gao, Jianming Ying, Jie He
Primary EGFR T790M mutation is occasionally identified by routine mutation testing in tyrosine kinase inhibitor (TKI)-naive patients with non-small cell lung cancer (NSCLC). We herein aimed to compare the characteristics of primary and acquired T790M mutations in NSCLC patients, and their response to osimertinib. Using amplification refractory mutation system (ARMS) detection, primary T790M was identified in 0.5% (46/8723) of TKI-naive patients, whereas acquired T790M was detected in 49.7% (71/143) of TKI-relapsed patients...
March 7, 2018: Cancer Letters
Francesco Passiglia, Sergio Rizzo, Christian Rolfo, Antonio Galvano, Enrico Bronte, Lorena Incorvaia, Angela Listi, Nadia Barraco, Marta Castiglia, Valentina Calo, Viviana Bazan, Antonio Russo
BACKGROUND: Recent studies evaluated the diagnostic accuracy of circulating tumor DNA (ctDNA) in the detection of epidermal growth factor receptor (EGFR) mutations from plasma of NSCLC patients, overall showing a high concordance as compared to standard tissue genotyping. However it is less clear if the location of metastatic site may influence the ability to identify EGFR mutations in plasma. OBJECTIVE: This pooled analysis aims to evaluate the association between the metastatic site location and the sensitivity of ctDNA analysis in detecting EGFR mutations in NSCLC patients...
March 8, 2018: Current Cancer Drug Targets
Weihua Li, Tian Qiu, Yun Ling, Shugeng Gao, Jianming Ying
Next-generation sequencing (NGS) has recently been rapidly adopted in the molecular diagnosis of cancer, but it still faces some obstacles. In this study, 665 lung adenocarcinoma samples (558 TKI-naive and 107 TKI-relapsed samples) were interrogated using NGS, and the challenges and possible solutions of subjecting appropriate tissue samples to NGS testing were explored. The results showed that lower frequencies of HER2/BRAF/PIK3CA and acquired EGFR T790M mutations were observed in biopsy samples with <20% tumor cellularity than those with ≥20%, but there were no significant differences in the frequencies of EGFR or KRAS mutations...
March 8, 2018: Molecular Oncology
Victor H F Lee
A 65-year-old female with diabetes mellitus but otherwise good health in the past suffered from cough with occasional blood-stained sputum during initial presentation. The patient was diagnosed with pulmonary poorly differentiated adenocarcinoma with an epidermal growth factor receptor (EGFR) exon 19 deletion and hence received afatinib therapy for 25 months without obvious adverse events except for a grade 1-2 acneiform rash. The disease was stabilized after subsequent cycles of chemotherapy with pemetrexed and carboplatin followed by maintenance pemetrexed...
March 2018: Asia-Pacific Journal of Clinical Oncology
B Melosky, N Blais, P Cheema, C Couture, R Juergens, S Kamel-Reid, M-S Tsao, P Wheatley-Price, Z Xu, D N Ionescu
Background: The development and approval of both targeted and immune therapies for patients with advanced non-small cell lung cancer (nsclc) has significantly improved patient survival rates and quality of life. Biomarker testing for patients newly diagnosed with nsclc, as well as for patients progressing after treatment with epidermal growth factor receptor ( EGFR ) inhibitors, is the standard of care in Canada and many parts of the world. Methods: A group of thoracic oncology experts in the field of thoracic oncology met to describe the standard for biomarker testing for lung cancer in the Canadian context, focusing on evidence-based recommendations for standard-of-care testing for EGFR , anaplastic lymphoma kinase ( ALK ), ROS1 , BRAF V600 and programmed death-ligand (PD-L1) at the time of diagnosis of advanced disease and EGFR T790M upon progression...
February 2018: Current Oncology
Zhe Yang, Nong Yang, Qiuxiang Ou, Yi Xiang, Tao Jiang, Xue Wu, Hua Bao, Xiaoling Tong, Xiaonan Wang, Yang W Shao, Yunpeng Liu, Yan Wang, Caicun Zhou
BACKGROUND:  The third generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat EGFR T790M-positive non-small cell lung cancer (NSCLC) patients who have developed resistance to earlier generation drugs. Acquired EGFR C797S mutation has been reported to mediate osimertinib-resistance in some patients. However, the remaining resistance mechanisms are largely unknown. METHODS: We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNA), and matched pre-treatment samples of 12 patients...
March 5, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Anna Buder, Maximilian J Hochmair, Sophia Schwab, Tatjana Bundalo, Peter Schenk, Peter Errhalt, Romana E Mikes, Gudrun Absenger, Kurt Patocka, Bernhard Baumgartner, Ulrike Setinek, Otto C Burghuber, Helmut Prosch, Robert Pirker, Martin Filipits
INTRODUCTION: Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated NSCLC who have been pre-treated with EGFR-TKIs. We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in clinical routine. METHODS: From April 2015 to November 2016, we included 119 patients with advanced EGFR-mutated NSCLC who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell-free plasma DNA by droplet digital PCR (ddPCR) in all patients and by tissue analyses in selected patients...
March 2, 2018: Journal of Thoracic Oncology
Chang-Guo Wang, Da-Xiong Zeng, Jian-An Huang, Jun-Hong Jiang
RATIONALE: The mechanism of the first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) acquired resistance included T790M mutation, cellular-mesenchymal to epithelial transition factor (MET) or EGFR amplification, PIK3CA mutation, and transformation to small cell lung cancer. MET amplification accounted for only about 5% of the resistance cases. PATIENTS CONCERNS: Few report detected MET amplification in pleural effusion. Here, we reported 2 lung adenocarcinoma cases with MET amplification in pleural effusion rapidly responded to crizotinib after EGFR-TKIs acquired resistance...
January 2018: Medicine (Baltimore)
Ling Wei, Li Xie, Xingwu Wang, Hongxin Ma, Liyan Lv, Lisheng Liu, Xianrang Song
Genotype-directed targeted therapy has become one of the standard treatment options for non-small cell lung cancer (NSCLC). There have been numerous limitations associated with mutation analysis of tissue samples. Consequently, mutational profile analysis of circulating cell-free DNA (cfDNA) by highly sensitive droplet digital PCR (ddPCR) assay has been developed. Possibly due to differences in cfDNA concentrations, previous studies have shown numerous discrepancies in mutation detection consistency between tissue and cfDNA...
March 1, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
Bo Zhang, Jianlin Xu, Xueyan Zhang, Ping Gu, Huimin Wang, Shuyuan Wang, Jie Qian, Rong Qiao, Yanwei Zhang, Wenjia Yang, Fangfei Qian, Yan Zhou, Jun Lu, Lele Zhang, Baohui Han
OBJECTIVES: Occasionally, primary 20 T790M/insertion plus sensitive mutations can be detected within a single tumor sample by routine molecular testing, but the optimal clinical management for these patients is unclear. Herein, we determined the optimal treatment strategy for these patients. MATERIALS AND METHODS: From January 2011 to January 2017, patients diagnosed with epidermal growth factor receptor (EGFR) mutation were screened. For these harboring primary 20 T790M/insertion plus sensitive mutations, the effectiveness of the first or third generation tyrosine kinase inhibitors (TKIs) were retrospectively analyzed...
March 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Ryo Ariyasu, Shingo Nishikawa, Ken Uchibori, Tomoko Oh-Hara, Takahiro Yoshizawa, Yosuke Dotsu, Junji Koyama, Masafumi Saiki, Tomoaki Sonoda, Satoru Kitazono, Noriko Yanagitani, Atsushi Horiike, Naohiko Inase, Kazuo Kasahara, Makoto Nishio, Ryohei Katayama
OBJECTIVES: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that can overcome resistance due to the Thr790Met (T790M) mutation. However, osimertinib occasionally shows limited efficacy in a small population of patients. We investigated the correlation between the ratio of T790M to EGFR activating mutation and the response to osimertinib. MATERIALS AND METHODS: Between April 2016 and April 2017, 44 patients started osimertinib therapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research...
March 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Jinxing Hu, Yufei Han, Jingtao Wang, Yue Liu, Yanfang Zhao, Yajing Liu, Ping Gong
Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of N-9-Diphenyl-9H-purin-2-amine derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 23a showed excellent enzyme inhibitory activities and selectivity with nanomolar IC50 values for both the single T790M and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 23a displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R...
February 17, 2018: Bioorganic & Medicinal Chemistry
Yao-Chen Wang, De-Wei Wu, Tzu-Chin Wu, Lee Wang, Chih-Yi Chen, Huei Lee
Resistance to tyrosine kinase inhibitors (TKIs) results in tumor relapse and poor prognosis in patients with lung adenocarcinoma. TKI resistance caused by epidermal growth factor receptor (EGFR) mutations at T790M and c-Met amplification occurs through persistent activation of the MEK/ERK and PI3K/AKT signaling pathways. We therefore expected that dual inhibitors of both signaling pathways could overcome TKI resistance in lung adenocarcinoma. Here, dioscin was selected from a product library of Chinese naturally occurring compounds and overcame TKI resistance in EGFR-mutated lung adenocarcinoma cells...
2018: International Journal of Biological Sciences
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