Article (Scientific journals)
Insights into ligand stimulation effects on gastro-intestinal stromal tumors signalling.
Bahlawane, Christelle; Schmitz, Martine; Letellier, Elisabeth et al.
2017In Cell Signal
Peer reviewed
 

Files


Full Text
Bahlawane et al., 2016.pdf
Publisher postprint (1.88 MB)
Download

All documents in ORBilu are protected by a user license.

Send to



Details



Abstract :
[en] Mutations in KIT or PDGFRA are responsible for >85% of gastrointestinal stromal tumors. The introduction of imatinib in the GIST therapy scheme revolutionized the patient outcome. Unfortunately, the therapy allows the disease stabilization instead of curation. Furthermore the resistance to the inhibitor arises in most cases within two first years of therapy. A thorough investigation of the signalling pathways activated by the major PDGFRA and KIT mutants encountered in the GIST landscape allowed to identify striking differences between the two receptor tyrosine kinases. PDGFRA mutants were not responsive to their ligand, PDGFAA, and displayed a high constitutive kinase activity. In contrast, all KIT mutants retained, in addition to their constitutive activation, the ability to be stimulated by their ligand. Kit mutants displayed a lower intrinsic kinase activity relative to PDGFRA mutants, while the KIT Exon 11 deletion mutant exhibited the highest intrinsic kinase activity among KIT mutants. At the transcriptomic level, the MAPK pathway was established as the most prominent activated pathway, which is commonly up-regulated by all PDGFRA and KIT mutants. Inhibition of this pathway, using the MEK inhibitor PD0325901, reduced the proliferation of GIST primary cells at nanomolar concentrations. Altogether, our data demonstrate the high value of MEK inhibitors for combination therapy in GIST treatment and more importantly the interest of evaluating the SCF expression profile in GIST patients presenting KIT mutations.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Bahlawane, Christelle
Schmitz, Martine ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Letellier, Elisabeth ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Arumugam, Karthik
Nicot, Nathalie
Nazarov, Petr
Haan, Serge ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
External co-authors :
no
Language :
English
Title :
Insights into ligand stimulation effects on gastro-intestinal stromal tumors signalling.
Publication date :
29 January 2017
Journal title :
Cell Signal
Peer reviewed :
Peer reviewed
Available on ORBilu :
since 10 September 2017

Statistics


Number of views
157 (15 by Unilu)
Number of downloads
175 (15 by Unilu)

Scopus citations®
 
5
Scopus citations®
without self-citations
4
OpenCitations
 
6
WoS citations
 
5

Bibliography


Similar publications



Contact ORBilu