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Oncogenic and ligand‐dependent activation of KIT/PDGFRA in surgical samples of imatinib‐treated gastrointestinal stromal tumours (GISTs)
Author(s) -
Negri T,
Bozzi F,
Conca E,
Brich S,
Gronchi A,
Bertulli R,
Fumagalli E,
Pierotti MA,
Tamborini E,
Pilotti S
Publication year - 2009
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2450
Subject(s) - pdgfra , autocrine signalling , imatinib , cancer research , paracrine signalling , platelet derived growth factor receptor , receptor tyrosine kinase , gist , proto oncogene proteins c kit , receptor , growth factor receptor , stromal cell , biology , tyrosine kinase , imatinib mesylate , growth factor , stem cell factor , microbiology and biotechnology , progenitor cell , stem cell , biochemistry , myeloid leukemia
As the range of receptor tyrosine kinase (RTK) inhibitors widens, a detailed understanding of the activating mechanisms of KIT/platelet‐derived growth factor receptor (PDGFR)A and the related downstream pathways involved in the development and maintenance of GISTs is becoming increasingly important. We analysed areas with different histological response ratios in surgical specimens taken from imatinib‐treated and untreated GIST patients in order to investigate KIT and PDGFRA expression/activation, the presence of their cognate ligands and the activation of downstream signalling, by means of biochemistry, immunohistochemistry and flow cytometry. All of the cases showed KIT and PDGFRA co‐expression. In addition to the oncogenic activation of mutated receptors, activation of wild‐type KIT and wild‐type PDGFRA, sustained by heterodimerization and an autocrine–paracrine loop, was demonstrated by the presence of their specific ligands, stem cell factor (SCF) and PDGFA. To confirm RTK activation further, all of the samples (including those with the highest regression ratios) were investigated for downstream effectors, and all proved to have activated downstream signalling. The results show that after the mutated receptors are switched off, heterologous wild‐type receptors become important in imatinib‐treated GISTs as a means of maintaining signalling activation. Taken together, our findings suggest that drugs targeting wild‐type receptors should be tested in imatinib‐treated GIST patients. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.