Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene.

Abstract

Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein-ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein-coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (TP53, IDH1, FBXW7, SDH-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST.

• Authors: Valentina Indio, Annalisa Astolfi, Giuseppe Tarantino, Milena Urbini, Janice Patterson, Margherita Nannini, Maristella Saponara, Lidia Gatto, Donatella Santini, Italo F do Valle, Gastone Castellani, Daniel Remondini, Michelangelo Fiorentino, Margaret von Mehren, Giovanni Brandi, Guido Biasco, Michael C Heinrich, Maria Aabbondanza Pantaleo
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 19 Issue 3 (Mar 04 2018) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 29510530 (Publication Type: Journal Article)

Chemical References

• Benzimidazoles
• F-Box-WD Repeat-Containing Protein 7
• FBXW7 protein, human
• Piperidines
• Protein Kinase Inhibitors
• Tumor Suppressor Protein p53
• Imatinib Mesylate
• Isocitrate Dehydrogenase
• IDH1 protein, human
• Electron Transport Complex II
• Receptor, Platelet-Derived Growth Factor alpha
• crenolanib

Topics

• Adult
• Aged
• Benzimidazoles (pharmacology)
• Drug Resistance, Neoplasm (genetics)
• Electron Transport Complex II (genetics, metabolism)
• F-Box-WD Repeat-Containing Protein 7 (genetics, metabolism)
• Female
• Gastrointestinal Neoplasms (genetics, metabolism)
• Gastrointestinal Stromal Tumors (genetics, metabolism)
• Humans
• Imatinib Mesylate (pharmacology)
• Isocitrate Dehydrogenase (genetics, metabolism)
• Male
• Middle Aged
• Mutation, Missense
• Piperidines (pharmacology)
• Protein Binding
• Protein Kinase Inhibitors (pharmacology)
• Protein Stability
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors, chemistry, genetics, metabolism)
• Transcriptome
• Tumor Suppressor Protein p53 (genetics, metabolism)