Linked Life Data

21132014

Source:http://linkedlifedata.com/resource/pubmed/id/21132014

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2011-4-7
pubmed:abstractText
Mesothelioma is an asbestos-associated and notoriously chemotherapy-resistant neoplasm. Activation of the receptor tyrosine kinases (RTKs), epidermal growth factor receptor and MET, has been described in subsets of mesothelioma, suggesting that TKs might represent therapeutic targets in this highly lethal disease. We employed proteomic screening by phosphotyrosine immunoaffinity purification and tandem mass spectrometry to characterize RTK activation in mesothelioma cell lines. These assays demonstrated expression and activation of the AXL protein, which is an RTK with known oncogenic properties in non-mesothelial cancer types. AXL was expressed and activated strongly in 8 of 9 mesothelioma cell lines and 6 of 12 mesothelioma biopsies, including each of 12 mesotheliomas with spindle-cell histology. Somatic AXL mutations were not found, but all mesotheliomas expressed an alternatively spliced AXL transcript with in-frame deletion of exon 10, and six of seven mesothelioma cell lines expressed the AXL ligand, growth arrest-specific 6 (GAS6). GAS6 expression appeared to be functionally relevant, as indicated by modulation of AXL tyrosine phosphorylation by knockdown of endogeneous GAS6, and by administration of exogenous GAS6. AXL silencing by lentivirus-mediated short hairpin RNA suppressed mesothelioma migration and cellular proliferation due to G1 arrest. The AXL inhibitor DP-3975 inhibited cell migration and proliferation in mesotheliomas with strong AXL activation. DP-3975 response in these tumors was characterized by inhibition of PI3-K/AKT/mTOR and RAF/MAPK signaling. AXL inhibition suppressed mesothelioma anchorage-independent growth, with reduction in colony numbers and size. These studies suggest that AXL inhibitors warrant clinical evaluation in mesothelioma.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1476-5594
pubmed:author
pubmed:issnType
Electronic
pubmed:day
7
pubmed:volume
30
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1643-52
pubmed:meshHeading
pubmed-meshheading:21132014-Alternative Splicing, pubmed-meshheading:21132014-Antineoplastic Agents, pubmed-meshheading:21132014-Cell Line, Tumor, pubmed-meshheading:21132014-Cell Movement, pubmed-meshheading:21132014-Cell Proliferation, pubmed-meshheading:21132014-Exons, pubmed-meshheading:21132014-Gene Silencing, pubmed-meshheading:21132014-Humans, pubmed-meshheading:21132014-Intercellular Signaling Peptides and Proteins, pubmed-meshheading:21132014-Mesothelioma, pubmed-meshheading:21132014-Neoplasm Invasiveness, pubmed-meshheading:21132014-Phosphorylation, pubmed-meshheading:21132014-Pleural Neoplasms, pubmed-meshheading:21132014-Proto-Oncogene Proteins, pubmed-meshheading:21132014-Receptor Protein-Tyrosine Kinases, pubmed-meshheading:21132014-Sequence Deletion, pubmed-meshheading:21132014-Signal Transduction
pubmed:year
2011
pubmed:articleTitle
AXL regulates mesothelioma proliferation and invasiveness.
pubmed:affiliation
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't