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Title: Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants
Authors: Debiec-Rychter, Maria
Cools, Jan
Dumez, Herlinde
Sciot, Raphael
Stul, Michel
Mentens, Nicole
Vranckx, Hilde
Wasag, Bartosz
Prenen, Hans
Roesel, Johannes
Hagemeijer-Hausman, Anne
Van Oosterom, Allan
Marynen, Peter # ×
Issue Date: Feb-2005
Publisher: W.B. Saunders
Series Title: Gastroenterology vol:128 issue:2 pages:270-279
Abstract: BACKGROUND AND AIMS: Resistance is a major challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). We investigated the mechanisms of resistance in patients with progressive GISTs with primary KIT mutations and the efficacy of the kinase inhibitor PKC412 for the inhibition of imatinib-resistant mutants. METHODS: We performed a cytogenetic analysis and screened for mutations of the KIT and PDGFRA kinase domains in 26 resistant GISTs. KIT autophosphorylation status was assessed by Western immunoblotting. Imatinib-resistant GIST cells and Ba/F3 cells expressing these mutant proteins were tested for sensitivity to imatinib and PKC412. RESULTS: Six distinct secondary mutations in KIT were detected in 12 progressive tumors, with V654A and T670I found to be recurrent. One progressive tumor showed acquired PDGFRA -D842V mutation. Amplification of KIT or KIT / PDGFRA was found in 2 patients. Eight of 10 progressive tumors available for analysis showed phosphorylated KIT. Two remaining progressive tumors lost KIT protein expression. GIST cells carrying KIT -del557-558/T670I or KIT -InsAY502-503/V654A mutations were resistant to imatinib, while PKC412 significantly inhibited autophosporylation of these mutants. Resistance to imatinib and sensitivity to PKC412 of KIT -T670I and PDGFRA -D842V mutants was confirmed using Ba/F3 cells. CONCLUSIONS: This study shows the high frequency of KIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of KIT / PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant KIT -T670I and KIT -V654A and of PDGFRA -D842V mutants to PKC412.
ISSN: 0016-5085
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Clinical Genetics Section (-)
Department of Oncology - miscellaneous
Laboratory for Neurofibromatosis Research
Translational Cell & Tissue Research
Laboratory of Experimental Oncology
Translational Research in GastroIntestinal Disorders
Laboratory for Genetics of Malignant Disorders
Clinical Digestive Oncology (+)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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