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cMET lung

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...
July 6, 2017: Clinical Lung Cancer
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
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
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
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
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
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
David Arguello, Andreas Voss, Zoran Gatalica, Ryan Bender
No abstract text is available yet for this article.
October 2016: Journal of Thoracic Oncology
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
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
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
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
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
Nele Van Der Steen, Elisa Giovannetti, Patrick Pauwels, Godefridus J Peters, David S Hong, Federico Cappuzzo, Fred R Hirsch, Christian Rolfo
The abnormal stimulation of the multiple signal transduction pathways downstream of the receptor tyrosine kinase mesenchymal-epithelial transition factor (cMET) promotes cellular transformation, tumor motility, and invasion. Therefore, cMET has been the focus of prognostic and therapeutic studies in different tumor types, including non-small cell lung cancer. In particular, several cMET inhibitors have been developed as innovative therapeutic candidates and are currently under investigation in clinical trials...
September 2016: Journal of Thoracic Oncology
Sheri L Moores, Mark L Chiu, Barbara S Bushey, Kristen Chevalier, Leopoldo Luistro, Keri Dorn, Randall J Brezski, Peter Haytko, Thomas Kelly, Sheng-Jiun Wu, Pauline L Martin, Joost Neijssen, Paul W H I Parren, Janine Schuurman, Ricardo M Attar, Sylvie Laquerre, Matthew V Lorenzi, G Mark Anderson
Non-small cell lung cancers (NSCLC) with activating EGFR mutations become resistant to tyrosine kinase inhibitors (TKI), often through second-site mutations in EGFR (T790M) and/or activation of the cMet pathway. We engineered a bispecific EGFR-cMet antibody (JNJ-61186372) with multiple mechanisms of action to inhibit primary/secondary EGFR mutations and the cMet pathway. JNJ-61186372 blocked ligand-induced phosphorylation of EGFR and cMet and inhibited phospho-ERK and phospho-AKT more potently than the combination of single receptor-binding antibodies...
July 1, 2016: Cancer Research
Shawn C Pun, Andrew Plodkowski, Matthew J Matasar, Yulia Lakhman, Darragh F Halpenny, Dipti Gupta, Chaya Moskowitz, Jiwon Kim, Richard Steingart, Jonathan W Weinsaft
BACKGROUND: Cardiac magnetic resonance (CMR) imaging is well validated for tissue characterization of cardiac masses but has not been applied to study pattern and prognostic implications of cardiac metastases (CMETs) among patients with systemic cancer. METHODS AND RESULTS: The population consisted of 60 patients with stage IV cancer (32 patients with CMETs, 28 diagnosis-matched controls) undergoing CMR. CMET was defined as a discrete mass with vascular tissue properties on delayed enhancement CMR...
May 2016: Journal of the American Heart Association
Ayman Oweida, Zeinab Sharifi, Hani Halabi, Yaoxian Xu, Siham Sabri, Bassam Abdulkarim
Stereotactic ablative radiotherapy (SABR) has emerged as a highly promising treatment for medically inoperable early-stage non-small cell lung cancer patients. Treatment outcomes after SABR have been excellent compared to conventional fractionated radiotherapy (CFRT). However, the biological determinants of the response to ablative doses of radiation remain poorly characterized. Furthermore, there's little data on the cellular and molecular response of genetically distinct NSCLC subtypes to radiation. We assessed the response of 3 genetically distinct lung adenocarcinoma cell lines to ablative and fractionated ionizing radiation (AIR and FIR)...
April 2, 2016: Cancer Biology & Therapy
Gregory Seedorf, Alexander J Metoxen, Robert Rock, Neil Markham, Sharon Ryan, Thiennu Vu, Steven H Abman
Impaired vascular endothelial growth factor (VEGF) signaling contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). We hypothesized that the effects of VEGF on lung structure during development may be mediated through its downstream effects on both endothelial nitric oxide synthase (eNOS) and hepatocyte growth factor (HGF) activity, and that, in the absence of eNOS, trophic effects of VEGF would be mediated through HGF signaling. To test this hypothesis, we performed an integrative series of in vitro (fetal rat lung explants and isolated fetal alveolar and endothelial cells) and in vivo studies with normal rat pups and eNOS(-/-) mice...
June 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Adrian G Sacher, Lisa W Le, Humberto Lara-Guerra, Thomas K Waddell, Shingo Sakashita, Zhuo Chen, Lucia Kim, Tong Zhang, Suzanne Kamel-Reid, Alexandra Salvarrey, Gail Darling, Kazuhiro Yasufuku, Shaf Keshavjee, Marc de Perrot, Frances A Shepherd, Geoffrey Liu, Ming Sound Tsao, Natasha B Leighl
BACKGROUND: Erlotinib is highly active in EGFR mutant NSCLC, but may benefit some with wild-type tumors. We examined pre-operative erlotinib in early stage NSCLC to assess response and correlation with potential biomarkers. RESULTS: Twenty-five patients were enrolled; 22 received erlotinib treatment and were evaluable (median follow-up 4.4 years). Histology was predominantly adenocarcinoma although 31% had squamous carcinoma. PET response was observed in 2 patients (9%), both with squamous carcinoma...
May 3, 2016: Oncotarget
Evangelos Tsiambas, Vasileios Ragos, Alicia Y Lefas, Stavros N Georgiannos, Dimitra Grapsa, Dimitra Grapsa, Efstratios Patsouris, Konstantinos Syrigos
Lung cancer exhibits an increasing incidence and a high mortality rate worldwide. Non-small cell lung carcinoma (NSCLC)constitutes the majority of patients with lung cancer (about 85% of all pathologically defined lung cancer cases). A broad spectrum of genomic imbalances, including chromosome polysomy/aneuploidy or specific gene deregulation mechanisms, such as point mutations, deletions and amplifications has been already identified in the corresponding patients, modifying their response rates to novel targeted therapeutic regimens, and affecting also their life span...
November 2015: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
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