title: Insights into ligand stimulation effects on gastro-intestinal stromal tumors signalling.
abstract: 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.
authors: Molecular Disease Mechanisms group, Life Sciences Research Unit, University of Luxembourg, Campus Belval, 6 Avenue du Swing, L-4367 Belvaux, Luxembourg. Electronic address: christelle.bahlawane@uni.lu.
authors: Christelle
authors: C
authors: Bahlawane
authors: Molecular Disease Mechanisms group, Life Sciences Research Unit, University of Luxembourg, Campus Belval, 6 Avenue du Swing, L-4367 Belvaux, Luxembourg.
authors: Martine
authors: M
authors: Schmitz
authors: Molecular Disease Mechanisms group, Life Sciences Research Unit, University of Luxembourg, Campus Belval, 6 Avenue du Swing, L-4367 Belvaux, Luxembourg.
authors: Elisabeth
authors: E
authors: Letellier
authors: Department of Infection and Immunity, LIH, 84 Val Fleuri, L-1526, Luxembourg.
authors: Karthik
authors: K
authors: Arumugam
authors: Genomics Research Unit, LIH, 84 Val Fleuri, L-1526, Luxembourg.
authors: Nathalie
authors: N
authors: Nicot
authors: Genomics Research Unit, LIH, 84 Val Fleuri, L-1526, Luxembourg.
authors: Petr V
authors: PV
authors: Nazarov
authors: Molecular Disease Mechanisms group, Life Sciences Research Unit, University of Luxembourg, Campus Belval, 6 Avenue du Swing, L-4367 Belvaux, Luxembourg.
authors: Serge
authors: S
authors: Haan
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D008024:Ligands; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: Gastro-intestinal stromal tumors; MAPK; PD0325901; PDGFRα; PI3K; c-KIT; stem cell factor