Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in approximately 5–7% of gastrointestinal stromal tumours (GIST). Over half of all PDGFRA mutations are represented by the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V), recognized as D842V, conferring primary resistance to imatinib in vitro and in clinical observations due to the conformation of the kinase domain, which negatively affects imatinib binding. The lack of interaction between imatinib and the D842V PDGFRA mutated model has been established and widely confirmed in vivo. However, for the other PDGFRA mutations, the correlation between pre-clinical and clinical data is still unclear. An in silico evaluation of the p.His845_Asn848delinsPro mutation involving exon 18 of PDGFRA in a metastatic GIST patient responding to first-line imatinib has been provided. Docking analyses were performed, and the ligand-receptor interactions were evaluated with the jCE algorithm for structural alignment. The docking simulation and structural superimposition analysis show that PDGFRA p.His845_Asn848delinsPro stabilizes the imatinib binding site with the residues that are conserved in KIT. The in vivo evidence that PDGFRA p.His845_Asn848delinsPro is sensitive to imatinib was confirmed by the molecular modelling, which may represent a reliable tool for the prediction of clinical outcomes and treatment selection in GIST, especially for rare mutations.

Molecular modelling evaluation of exon 18 His845_Asn848delinsPro pDGFRα mutation in a metastatic GIST patient responding to imatinib

Margherita Nannini;Giuseppe Tarantino;Valentina Indio;Gloria Ravegnini;Annalisa Astolfi;Milena Urbini;Antonio De Leo;Claudio Ceccarelli;Elisa Gruppioni;Paolo Castellucci;Stefano Fanti;Maristella Saponara;Lidia Gatto;Andrea Pession;Pier Luigi Martelli;Rita Casadio;Maria Abbondanza Pantaleo
2019

Abstract

Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in approximately 5–7% of gastrointestinal stromal tumours (GIST). Over half of all PDGFRA mutations are represented by the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V), recognized as D842V, conferring primary resistance to imatinib in vitro and in clinical observations due to the conformation of the kinase domain, which negatively affects imatinib binding. The lack of interaction between imatinib and the D842V PDGFRA mutated model has been established and widely confirmed in vivo. However, for the other PDGFRA mutations, the correlation between pre-clinical and clinical data is still unclear. An in silico evaluation of the p.His845_Asn848delinsPro mutation involving exon 18 of PDGFRA in a metastatic GIST patient responding to first-line imatinib has been provided. Docking analyses were performed, and the ligand-receptor interactions were evaluated with the jCE algorithm for structural alignment. The docking simulation and structural superimposition analysis show that PDGFRA p.His845_Asn848delinsPro stabilizes the imatinib binding site with the residues that are conserved in KIT. The in vivo evidence that PDGFRA p.His845_Asn848delinsPro is sensitive to imatinib was confirmed by the molecular modelling, which may represent a reliable tool for the prediction of clinical outcomes and treatment selection in GIST, especially for rare mutations.
SCIENTIFIC REPORTS
Margherita Nannini, Giuseppe Tarantino , Valentina Indio, Gloria Ravegnini, Annalisa Astolfi, Milena Urbini, Antonio De Leo, Donatella Santini, Claudio Ceccarelli, Elisa Gruppioni, Annalisa Altimari, Paolo Castellucci, Stefano Fanti, Valerio Di Scioscio, Maristella Saponara, Lidia Gatto, Andrea Pession, Pier Luigi Martelli, Rita Casadio, Maria Abbondanza Pantaleo
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/667410
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