Read by QxMD icon Read


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
Zheng-Hai Tang, Jin-Jian Lu
Given the successful identification of epidermal growth factor receptor EGFR T790M, the third-generation EGFR tyrosine kinase inhibitor (TKI), osimertinib (OSI, AZD9291), was developed to target EGFR T790M mutation. OSI was approved for the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR T790M mutation. However, the disease would progress after the patient received OSI treatment for approximately 10 months. Resistance mechanisms to OSI, such as additional mutation of EGFR and alternative kinase activation, were recently identified, and some novel therapeutic strategies were proposed to overcome OSI resistance...
April 28, 2018: Cancer Letters
Yutao Liu, Xuezhi Hao, Xingsheng Hu, Junling Li, Yan Wang, Hongyu Wang, Puyuan Xing, Weihua Li, Jianming Ying, Xiaohong Han, Yuankai Shi
Osimertinib is a novel, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor targeting EGFR mutations and the EGFR T790 mutation. Here, we report a woman with EGFR-mutated lung adenocarcinoma who, after 23-month treatment with gefitinib, developed the EGFR T790M mutation, which converted the T790M status from positive to negative before osimertinib treatment and developed MET amplification, leading to rapid progression on osimertinib in two months. Subsequent treatment with crizotinib and c-Met inhibitor plus gefitinib also failed to improve the clinical outcome, suggesting the potential existence of another resistance mechanism...
February 7, 2018: Thoracic Cancer
Xiaoyun Lu, Lei Yu, Zhang Zhang, Xiaomei Ren, Jeff B Smaill, Ke Ding
Both the first-generation reversible epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib and the second-generation covalent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib have significantly improved the survival of non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, a secondary EGFRT790M mutation leads to the clinically acquired resistance to the first- and second-generation EGFR-TKIs drugs. A number of the third-generation wild-type sparing EGFR inhibitors, for example, WZ4002, CO1686, AZD9291, HM61713, EGF816, ASP8173, and PF0674775, have been developed, among which AZD9291 has been approved by US FDA for the treatment of NSCLC patients with EGFRT790M ...
January 26, 2018: Medicinal Research Reviews
Shenghai Wu, Lucheng Zhu, Linglan Tu, Sumei Chen, Haixiu Huang, Jingjing Zhang, Shenglin Ma, Shirong Zhang
AZD9291 is a novel, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which is administered orally. It has been proven effective in non-small cell lung cancer (NSCLC) patients, with both EGFR-sensitizing and EGFR T790M mutations in preclinical models. However, the potential therapeutic effects of AZD9291 combined with other modalities, including ionizing radiation, are not well understood. The presence of AZD9291 significantly increases the cell-killing effects of radiation in PC-9-IR cells with a secondary EGFR mutation (T790M), which was developed from NSCLC PC-9 cells (human lung adenocarcinoma cell with EGFR 19 exon 15 bp deletion) after chronic exposure to increasing doses of gefitinib, and in H1975 cells (human lung adenocarcinoma cell with EGFR exon 20 T790M mutation de novo), but not in PC-9 cells or in H460 cells (human lung adenocarcinoma cell with wild-type EGFR)...
January 13, 2018: Radiation Research
Shengwu Liu, Shuai Li, Josephine Hai, Xiaoen Wang, Ting Chen, Max M Quinn, Peng Gao, Yanxi Zhang, Hongbin Ji, Darren Cross, Kwok-Kin Wong
PURPOSE: HER2 (or ERBB2) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2-6 percent of lung adenocarcinomas. HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). However, due to limited preclinical studies and clinical trials, currently there is still no available standard of care for lung cancer patients with HER2 aberrations. To fulfill the clinical need for targeting HER2 in non-small cell lung cancer (NSCLC) patients, we performed a comprehensive pre-clinical study to evaluate the efficacy of a third-generation TKI, osimertinib (AZD9291)...
January 3, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Maicol Mancini, Hilah Gal, Nadège Gaborit, Luigi Mazzeo, Donatella Romaniello, Tomer Meir Salame, Moshit Lindzen, Georg Mahlknecht, Yehoshua Enuka, Dominick Ga Burton, Lee Roth, Ashish Noronha, Ilaria Marrocco, Dan Adreka, Raya Eilam Altstadter, Emilie Bousquet, Julian Downward, Antonio Maraver, Valery Krizhanovsky, Yosef Yarden
Epidermal growth factor receptor ( EGFR ) mutations identify patients with lung cancer who derive benefit from kinase inhibitors. However, most patients eventually develop resistance, primarily due to the T790M second-site mutation. Irreversible inhibitors (e.g., osimertinib/AZD9291) inhibit T790M-EGFR, but several mechanisms, including a third-site mutation, C797S, confer renewed resistance. We previously reported that a triple mixture of monoclonal antibodies, 3×mAbs, simultaneously targeting EGFR, HER2, and HER3, inhibits T790M-expressing tumors...
February 2018: EMBO Molecular Medicine
Xiaoyan Shen, Jie Shen, Hang Zhang, Yuxin Cheng, Yang Yang, Jiahui Gao, Yu Zhang, Rutian Li, Baorui Liu, Lifeng Wang
Driver mutation detection and the development of targeted drugs have significantly improved survival of advanced lung adenocarcinoma patients with driver mutations. However, we still lack understanding of druggable mutations in patients with advanced squamous cell lung cancer (SQCLC). Less than 10% of SQCLC patients have EGFR gene mutations, thus we have limited knowledge of biological molecular changes with first generation EGFR-tyrosine kinase inhibitor (TKI) resistance. We report a case of an SQCLC patient treated with first-line platinum-doublet chemotherapy...
November 16, 2017: Thoracic Cancer
Yeong Hoon Kim, Lokraj Bhatt, Hye-Jin Ahn, Zhaoshou Yang, Won-Kyu Lee, Ho-Woo Nam
The effects of tyrosine kinase inhibitors (TKIs) were evaluated on growth inhibition of intracellular Toxoplasma gondii in host ARPE-19 cells. The number of tachyzoites per parasitophorous vacuolar membrane (PVM) was counted after treatment with TKIs. T. gondii protein expression was assessed by western blot. Immunofluorescence assay was performed using Programmed Cell Death 4 (PDCD4) and T. gondii GRA3 antibodies. The TKIs were divided into 3 groups; non-epidermal growth factor receptor (non-EGFR), anti-human EGFR 2 (anti-HER2), and anti-HER2/4 TKIs, respectively...
October 2017: Korean Journal of Parasitology
Sherry Niessen, Melissa M Dix, Sabrina Barbas, Zachary E Potter, Shuyan Lu, Oleg Brodsky, Simon Planken, Douglas Behenna, Chau Almaden, Ketan S Gajiwala, Kevin Ryan, RoseAnn Ferre, Michael R Lazear, Matthew M Hayward, John C Kath, Benjamin F Cravatt
Patients with non-small cell lung cancers that have kinase-activating epidermal growth factor receptor (EGFR) mutations are highly responsive to first- and second-generation EGFR inhibitors. However, these patients often relapse due to a secondary, drug-resistant mutation in EGFR whereby the gatekeeper threonine is converted to methionine (T790M). Several third-generation EGFR inhibitors have been developed that irreversibly inactivate T790M-EGFR while sparing wild-type EGFR, thus reducing epithelium-based toxicities...
November 16, 2017: Cell Chemical Biology
Xiao-Ming Jiang, Yu-Lian Xu, Mu-Yang Huang, Le-Le Zhang, Min-Xia Su, Xiuping Chen, Jin-Jian Lu
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In NSCLC patients, an EGFR mutation is likely to be correlated with high levels of expression of programmed death ligand-1 (PD-L1). Here, we showed that osimertinib decreased PD-L1 expression in human EGFR mutant NSCLC cells in vitro. Osimertinib (125 nmol/L) markedly suppressed PD-L1 mRNA expression in both NCI-H1975 and HCC827 cells...
November 2017: Acta Pharmacologica Sinica
Osamu Takakuwa, Tetsuya Oguri, Takehiro Uemura, Kazuki Sone, Satoshi Fukuda, Minami Okayama, Yoshihiro Kanemitsu, Hirotsugu Ohkubo, Masaya Takemura, Yutaka Ito, Ken Maeno, Akio Niimi
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for EGFR-T790M-positive non-small cell lung cancer. A high incidence of interstitial lung disease (ILD) during combination treatment with osimertinib and anti-programmed cell death-ligand 1 (PD-L1) inhibitor has been reported. The current study presents a case of ILD development during osimertinib treatment following nivolumab (an anti-PD-1 antibody) treatment. The 59-year-old female was diagnosed with stage IV lung adenocarcinoma harboring a deletion in exon 19 of the EGFR gene...
September 2017: Molecular and Clinical Oncology
Puyu Shi, You-Take Oh, Liang Deng, Guojing Zhang, Guoqing Qian, Shuo Zhang, Hui Ren, Grant Wu, Benjamin Legendre, Emily Anderson, Suresh S Ramalingam, Taofeek K Owonikoko, Mingwei Chen, Shi-Yong Sun
Purpose: The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO), an approved third-generation EGFR inhibitor, in EGFR-mutant non-small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study.Experimental Design: AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytometry...
November 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Zheng-Hai Tang, Min-Xia Su, Xia Guo, Xiao-Ming Jiang, Lin Jia, Xiuping Chen, Jin-Jian Lu
BACKGROUND: Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients. OBJECTIVE: Establishment of the OSI-resistant HCC827/OSIR cell line and study of its resistant mechanism. METHOD: The anti-proliferative effect was studied through MTT and colony formation assays. The protein expression was detected by Western blot assay...
July 19, 2017: Anti-cancer Agents in Medicinal Chemistry
Simon Dearden, Helen Brown, Suzanne Jenkins, Kenneth S Thress, Mireille Cantarini, Rebecca Cole, Malcolm Ranson, Pasi A Jänne
OBJECTIVES: Reliable epidermal growth factor receptor (EGFR) mutation testing techniques are required to identify eligible patients with EGFR mutation/T790M positive advanced non-small cell lung cancer (NSCLC), for treatment with osimertinib (AZD9291), an oral, potent, irreversible EGFR tyrosine kinase inhibitor (TKI) selective for EGFR-TKI-sensitizing and T790M resistance mutations over wild-type EGFR. There is no current consensus regarding the best method to detect EGFR T790M mutations...
July 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Shaon Chakrabarti, Franziska Michor
The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes...
July 15, 2017: Cancer Research
Lu-Lu Kong, Rui Ma, Ming-Yu Yao, Xiao-E Yan, Su-Jie Zhu, Peng Zhao, Cai-Hong Yun
Drug-resistance is a major challenge in targeted therapy of EGFR mutated non-small cell lung cancers (NSCLCs). The third-generation irreversible inhibitors such as AZD9291, CO-1686 and WZ4002 can overcome EGFR T790M drug-resistance mutant through covalent binding through Cys 797, but ultimately lose their efficacy upon emergence of the new mutation C797S. To develop new reversible inhibitors not relying on covalent binding through Cys 797 is therefore urgently demanded. Gö6976 is a staurosporine-like reversible inhibitor targeting T790M while sparing the wild-type EGFR...
June 24, 2017: Biochemical and Biophysical Research Communications
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...
July 28, 2017: European Journal of Medicinal Chemistry
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...
May 30, 2017: Oncotarget
Nibal Saad, Aarati Poudel, Alina Basnet, Ajeet Gajra
Adenocarcinoma is the most common type of non-small-cell lung cancer (NSCLC). Adenocarcinoma with epidermal growth factor receptor (EGFR) mutations accounts for 8%-30% of all cases of NSCLC depending on the geography and ethnicity. EGFR-mutated NSCLC usually responds to first-line therapy with EGFR tyrosine kinase inhibitors (TKIs). However, there is eventual loss of efficacy to TKIs due to development of resistance. The most frequent cause for resistance is a second EGFR mutation in exon 20 (T790M), which is encountered in up to 62% of patients...
2017: OncoTargets and Therapy
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"