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https://www.readbyqxmd.com/read/29616327/whole-exome-sequencing-identifies-key-mutated-genes-in-t790m-wildtype-cmet-unamplified-lung-adenocarcinoma-with-acquired-resistance-to-first-generation-egfr-tyrosine-kinase-inhibitors
#1
Chenguang Li, Hailin Liu, Bin Zhang, Liqun Gong, Yanjun Su, Zhenfa Zhang, Changli Wang
PURPOSE: Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma harboring EGFR-activating mutations will inevitably acquire resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs). EGFR T790M mutation and cMET amplification are common mechanisms. Further study is needed to explore unknown genomic alterations contributing to drug resistance. METHODS: Tumor and blood samples from 69 stage IIIB-IV NSCLC patients defined as acquired resistance to first-generation EGFR TKIs (gefitinib, erlotinib or ecotinib) were collected...
April 3, 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29602831/bioengineered-ncrnas-selectively-change-cellular-mirnome-profiles-for-cancer-therapy
#2
Pui Yan Ho, Zhijian Duan, Neelu Batra, Joseph L Jilek, Mei-Juan Tu, Jing-Xin Qiu, Zihua Hu, Theodore Wun, Primo N Lara, Ralph W DeVere White, Hong-Wu Chen, Ai-Ming Yu
Noncoding RNAs (ncRNAs) produced in live cells may better reflect intracellular ncRNAs for research and therapy. Attempts were made to produce biological ncRNAs, but at low yield or success rate. Here we first report a new ncRNA bioengineering technology, using more stable ncRNA carrier (nCAR) containing a pre-miR-34a derivative identified by rational design and experimental validation. This approach offered a remarkable higher-level expression (40-80% of total RNAs) of recombinant ncRNAs in bacteria, and gave an 80% success rate (33 out of 42 ncRNAs)...
March 30, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29507702/does-molecular-profiling-of-tumors-using-the-caris-molecular-intelligence-platform-improve-outcomes-for-cancer-patients
#3
Philip Carter, Costi Alifrangis, Biancastella Cereser, Pramodh Chandrasinghe, Lisa Del Bel Belluz, Thomas Herzog, Joel Levitan, Nina Moderau, Lee Schwartzberg, Neha Tabassum, Jinrui Wen, Jonathan Krell, Justin Stebbing
We evaluated the effect of tailoring treatments based on predictions informed by tumor molecular profiles across a range of cancers, using data from Caris Life Sciences. These included breast carcinoma, colorectal adenocarcinoma, female genital tract malignancy, lung non-small cell lung cancer, neuroendocrine tumors, ovarian surface epithelial carcinomas, and urinary tract cancers. Molecular profiles using mostly immunohistochemistry (IHC) and DNA sequencing for tumors from 841 patients had been previously used to recommend treatments; some physicians followed the suggestions completely while some did not...
February 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29249325/outcomes-in-patients-with-non-small-cell-lung-cancer-and-acquired-thr790met-mutation-treated-with-osimertinib-a-genomic-study
#4
Chia-Chi Lin, Jin-Yuan Shih, Chong-Jen Yu, Chao-Chi Ho, Wei-Yu Liao, Jih-Hsing Lee, Tzu-Hsiu Tsai, Kang-Yi Su, Min-Shu Hsieh, Yih-Leong Chang, Ya-Ying Bai, Derek De-Rui Huang, Kenneth S Thress, James Chih-Hsin Yang
BACKGROUND: Osimertinib is approved for the treatment of non-small-cell lung cancer in patients who develop the EGFR Thr790Met mutation after treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). We assessed outcomes in patients with non-small-cell lung cancer and the EGFR Thr790Met mutation who were treated with osimertinib, a third-generation EGFR TKI, after previous treatment failure with one or more other EGFR TKIs. METHODS: Eligible patients had been enrolled at one centre in the AURA study, had shown resistance to a previous EGFR TKI, and had EGFR-activating mutations and acquired Thr790Met mutation detectable in tumour tissue or plasma...
February 2018: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/29199685/role-of-crizotinib-in-c-mesenchymal-epidermal-transition-positive-nonsmall-cell-lung-cancer-patients
#5
U Batra, A Jain, M Sharma, R Bajaj, M Suryavanshis
The increasing cases of NSCLC and improved understanding of its molecular biology has lead to identification of its varied driver mutations. cMET amplification has an important role as resistance mechanism for EGFR TKIs. Crizotinib is a drug which shows its anti-tumoral effect in cMET positive cases. Here we present a case series of three such patients who achieved were cMET amplified and showed partial response on Crizotinib.
January 2017: Indian Journal of Cancer
https://www.readbyqxmd.com/read/29061221/-advances-in-the-transformation-to-small-cell-lung-cancer-from-non-small-cell-lung-cancer-following-acquired-drug-resistance-to-egfr-tyrosine-kinase-inhibitors
#6
REVIEW
Wenqiu Zhang, Yongqi Li, Di Wu
The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of sensitive EGFR mutation in non-small cell lung cancer (NSCLC) has been proved significant curative effect. However, the acquisition of the drug resistance to EGFR-TKIs is almost inevitable, and common drug resistance mechanisms include T790M mutation, cMET amplification, etc. One of the rare resistance mechanisms of EGFR-TKIs is the transformation from NSCLC into small cell lung cancer (SCLC), which account for about 3%-15%...
October 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/28915692/biomarker-analysis-of-the-phase-3-torch-trial-for-first-line-erlotinib-versus-chemotherapy-in-advanced-non-small-cell-lung-cancer-patients
#7
Lucia Kim, Mauro Saieg, Massimo Di Maio, Ciro Gallo, Charles Butts, Fortunato Ciardiello, Ronald Feld, Dengxiao Cheng, Vittorio Gebbia, Marco Angelo Burgio, Yasmin Alam, Simona Signoriello, Antonio Rossi, Natasha Leighl, Paolo Maione, Alessandro Morabito, Geoffrey Liu, Ming-Sound Tsao, Francesco Perrone, Cesare Gridelli
BACKGROUND: The TORCH phase III trial compared the efficacy of first-line erlotinib followed by chemotherapy at progression (experimental arm) with the reverse sequence (standard arm) in unselected advanced non-small cell lung cancer (NSCLC) patients. Here we report biomarker analyses. METHODS: EGFR and KRAS mutation, expression of EGFR family members and of cMET and PTEN and EGFR and ABCG2 germline polymorphisms were tested on tumor tissue or blood samples to either confirm previously proposed predictive role or describe it in an explorative setting...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28757336/double-trouble-a-case-series-on-concomitant-genetic-aberrations-in-nsclc
#8
REVIEW
Nele Van Der Steen, Yves Mentens, Marc Ramael, Leticia G Leon, Paul Germonpré, Jose Ferri, David R Gandara, Elisa Giovannetti, Godefridus J Peters, Patrick Pauwels, Christian Rolfo
Several oncogenic drivers have been identified in non-small cell lung cancer. Targeted therapies for these aberrations have already been successfully developed and implemented in clinical practice. Owing to improved sensitivity in genetic testing, more and more tumors with multiple driver mutations are identified, resulting in dilemmas for treating physicians whether and which targeted therapy to use. In this case series, we provide an overview of patients with intrinsic double mutations in oncogenic drivers and their reported response to targeted therapies, with a focus on epidermal growth factor receptor, anaplastic lymphoma kinase, cMET, and Kirsten rat sarcoma viral oncogene...
January 2018: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28673967/piperlongumine-induces-reactive-oxygen-species-ros-dependent-downregulation-of-specificity-protein-transcription-factors
#9
Keshav Karki, Erik Hedrick, Ravi Kasiappan, Un-Ho Jin, Stephen Safe
Piperlongumine is a natural product found in the plant species Piper longum , and this compound exhibits potent anticancer activity in multiple tumor types and has been characterized as an inducer of reactive oxygen species (ROS). Treatment of Panc1 and L3.6pL pancreatic, A549 lung, 786-O kidney, and SKBR3 breast cancer cell lines with 5 to 15 μmol/L piperlongumine inhibited cell proliferation and induced apoptosis and ROS, and these responses were attenuated after cotreatment with the antioxidant glutathione...
August 2017: Cancer Prevention Research
https://www.readbyqxmd.com/read/28427160/biomarker-analysis-of-the-phase-3-torch-trial-for-first-line-erlotinib-versus-chemotherapy-in-advanced-non-small-cell-lung-cancer-patients
#10
Lucia Kim, Mauro Saieg, Massimo Di Maio, Ciro Gallo, Charles Butts, Fortunato Ciardiello, Ronald Feld, Dengxiao Cheng, Vittorio Gebbia, Marco Angelo Burgio, Yasmin Alam, Simona Signoriello, Antonio Rossi, Natasha Leighl, Paolo Maione, Alessandro Morabito, Geoffrey Liu, Ming-Sound Tsao, Francesco Perrone, Cesare Gridelli
BACKGROUND: The TORCH phase III trial compared the efficacy of first-line erlotinib followed by chemotherapy at progression (experimental arm) with the reverse sequence (standard arm) in unselected advanced non-small cell lung cancer (NSCLC) patients. Here we report biomarker analyses. METHODS: EGFR and KRAS mutation, expression of EGFR family members and of cMET and PTEN and EGFR and ABCG2 germline polymorphisms were tested on tumor tissue or blood samples to either confirm previously proposed predictive role or describe it in an explorative setting...
February 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28362115/novel-egfr-t790m-cmet-dual-inhibitors-putative-therapeutic-agents-for-non-small-cell-lung-cancer
#11
Pankaj Kumar Singh, Om Silakari
AIM: Different resistance mechanisms, especially, T790M secondary acquired point mutation and in some cases amplification of cMET, have been a major setback for the lung cancer therapies. METHODOLOGY: The current in silico study explored the small molecules which can act as putative EGFR (T790M)-cMET dual inhibitors. Databases were first filtered and subsequently cross filtered, initially by thoroughly validated pharmacophore models for both targets. As per score and interactions obtained in docking, the molecules were subjected to molecular dynamics simulations, to study the stability and binding orientations of their complexes with target proteins...
April 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28143872/musashi-rna-binding-proteins-as-cancer-drivers-and-novel-therapeutic-targets
#12
REVIEW
Alexander E Kudinov, John Karanicolas, Erica A Golemis, Yanis Boumber
Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. Although much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act posttranscriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBP) Musashi-1 (MSI1) and Musashi-2 (MSI2) are emerging as regulators of multiple critical biological processes relevant to cancer initiation, progression, and drug resistance...
May 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28008383/better-to-be-alone-than-in-bad-company-the-antagonistic-effect-of-cisplatin-and-crizotinib-combination-therapy-in-non-small-cell-lung-cancer
#13
Nele Van Der Steen, Christophe Deben, Vanessa Deschoolmeester, An Wouters, Filip Lardon, Christian Rolfo, Paul Germonpré, Elisa Giovannetti, Godefridus J Peters, Patrick Pauwels
AIM: To investigate the potential benefit of combining the cMET inhibitor crizotinib and cisplatin we performed in vitro combination studies. METHODS: We tested three different treatment schemes in four non-small cell lung cancer (NSCLC) cell lines with a different cMET/epidermal growth factor receptor genetic background by means of the sulforhodamine B assay and performed analysis with Calcusyn. RESULTS: All treatment schemes showed an antagonistic effect in all cell lines, independent of the cMET status...
December 10, 2016: World Journal of Clinical Oncology
https://www.readbyqxmd.com/read/27801981/heterogeneity-of-the-resistance-to-gefitinib-treatment-in-a-non-small-cell-lung-cancer-patient-with-active-epidermal-growth-factor-receptor-mutation
#14
Chong-Rui Xu, Wen-Zhao Zhong, Qing Zhou, Xu-Chao Zhang, Jin-Ji Yang, Yi-Long Wu
We report the case of a 37-year-old male non-small cell lung cancer patient with an active epidermal growth factor receptor (EGFR) mutation who received gefitinib as first-line treatment. After 13.7 months, the patient experienced disease progression and was treated with platinum-based doublet chemotherapy plus gefitinib for 5.4 months. A subsequent lung biopsy showed cMET overexpression; therefore, the patient received a cMET inhibitor with the gefitinib. The response in the different lesions of several organs was diverse...
January 2017: Thoracic Cancer
https://www.readbyqxmd.com/read/27676475/o-04-profiling-of-met-amplified-non-small-cell-lung-cancer-nsclc-correlation-to-cmet-protein-expression-met-exon-14-skipping
#15
David Arguello, Andreas Voss, Zoran Gatalica, Ryan Bender
No abstract text is available yet for this article.
October 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27573756/crizotinib-resistance-implications-for-therapeutic-strategies
#16
REVIEW
I Dagogo-Jack, A T Shaw
In 2007, a chromosomal rearrangement resulting in a gene fusion leading to expression of a constitutively active anaplastic lymphoma kinase (ALK) fusion protein was identified as an oncogenic driver in non-small-cell lung cancer (NSCLC). ALK rearrangements are detected in 3%-7% of patients with NSCLC and are particularly enriched in younger patients with adenocarcinoma and a never or light smoking history. Fortuitously, crizotinib, a small molecule tyrosine kinase inhibitor initially developed to target cMET, was able to be repurposed for ALK-rearranged (ALK+) NSCLC...
September 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27566252/genomic-alterations-in-neuroendocrine-cancers-of-the-ovary
#17
George Yaghmour, Philippe Prouet, Eric Wiedower, Omer Hassan Jamy, Rebecca Feldman, Jason C Chandler, Manjari Pandey, Mike G Martin
BACKGROUND: As we have previously reported, small cell carcinoma of the ovary (SCCO) is a rare, aggressive form of ovarian cancer associated with poor outcomes. In an effort to identify new treatment options, we utilized comprehensive genomic profiling to assess the potential for novel therapies in SCCO. METHODS: Patients with SCCO, SCCO-HT (hypercalcemic type), neuroendocrine tumors of the ovary (NET-O), and small cell carcinoma of the lung (SCLC) profiled by Caris Life Sciences between 2007-2015 were identified...
August 26, 2016: Journal of Ovarian Research
https://www.readbyqxmd.com/read/27546183/dual-transcript-and-protein-quantification-in-a-massive-single-cell-array
#18
Seung-Min Park, Jae Young Lee, Soongweon Hong, Sang Hun Lee, Ivan K Dimov, Hojae Lee, Susie Suh, Qiong Pan, Keyu Li, Anna M Wu, Shannon M Mumenthaler, Parag Mallick, Luke P Lee
Recently, single-cell molecular analysis has been leveraged to achieve unprecedented levels of biological investigation. However, a lack of simple, high-throughput single-cell methods has hindered in-depth population-wide studies with single-cell resolution. We report a microwell-based cytometric method for simultaneous measurements of gene and protein expression dynamics in thousands of single cells. We quantified the regulatory effects of transcriptional and translational inhibitors on cMET mRNA and cMET protein in cell populations...
October 7, 2016: Lab on a Chip
https://www.readbyqxmd.com/read/27362807/tc-n19-a-novel-dual-inhibitor-of-egfr-and-cmet-efficiently-overcomes-egfr-tki-resistance-in-non-small-cell-lung-cancer-cells
#19
D-W Wu, T-C Chen, H-S Huang, H Lee
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show a clinical benefit when used to treat patients with EGFR-mutated non-small-cell lung cancer (NSCLC), but this treatment unfortunately fails in patients with TKI-resistant tumors. We here provide evidence that TC-N19 (N19), a novel dual inhibitor of EGFR and cMET, efficiently overcomes the EGFR-TKI resistance in EGFR-mutated NSCLC cells via simultaneous degradation of both proteins by ubiquitin proteasomes. Comparison with HSP90 inhibitor treatment and knockdown of EGFR and cMET by small hairpin RNAs reveal that the reduction of EGFR and cMET expression by N19 is responsible for overcoming the intrinsic TKI resistance mediated by paxillin (PXN) in high PXN-expressing cells, PXN-overexpressing PC9 cells (PC9-PXN), the EGFR-T790M-mediated TKI resistance in H1975 and CL97 cells, and the acquired resistance to gefitinib in gefitinib-resistant PC9 cells (PC9GR)...
June 30, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27329168/genomic-landscape-of-small-cell-carcinoma-of-the-breast-contrasted-to-small-cell-carcinoma-of-the-lung
#20
COMPARATIVE STUDY
Brennan McCullar, Manjari Pandey, George Yaghmour, Felicia Hare, Kruti Patel, Matthew Stein, Rebecca Feldman, Jason C Chandler, Michael G Martin
Small cell carcinoma of the breast is a rare, aggressive form of breast cancer that is associated with extremely poor outcomes [1]. In an effort to identify possible targets for treatment, we utilized comprehensive genomic profiling in small cell carcinoma of the breast. Under an IRB approved protocol, we identified patients with small cell carcinoma of the breast and small cell carcinoma of the lung profiled by Caris Life Sciences between 2007 and 2015. Tumors were assessed with up to 25 immunohistochemical stains, in situ hybridization of cMET, EGFR, HER2, PIK3CA, and TOP2A, and next generation sequencing as well as Sanger sequencing of 47 genes...
July 2016: Breast Cancer Research and Treatment
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