Insights into ligand stimulation effects on gastro-intestinal stromal tumors signalling

Christelle Bahlawane*, Martine Schmitz, Elisabeth Letellier, Karthik Arumugam, Nathalie Nicot, Petr V. Nazarov, Serge Haan

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)138-149
Number of pages12
JournalCellular Signalling
Volume29
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • Gastro-intestinal stromal tumors
  • MAPK
  • PD0325901
  • PDGFRα
  • PI3K
  • c-KIT
  • stem cell factor

Fingerprint

Dive into the research topics of 'Insights into ligand stimulation effects on gastro-intestinal stromal tumors signalling'. Together they form a unique fingerprint.

Cite this