Reference Detail

Ref Type Journal Article
PMID (15928335)
Authors Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, Shiraga S, Bainbridge T, Morich J, Heinrich MC
Title PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.
Journal Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Vol 23
Issue 23
Date 2005 Aug 10
URL
Abstract Text Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs.We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing.66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings.Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
D842_D846del deletion gain of function - predicted PDGFRA D842_D846del results in the deletion of five amino acids in the protein kinase domain of the Pdgfra protein from amino acids 842 to 846 (UniProt.org). D842_D846del has been identified in the scientific literature (PMID: 26130666), but has not been biochemically characterized, however, similar PDGFRA exon 18 deletions are activating (PMID: 12522257, PMID: 15928335) and therefore, is predicted to result in a gain of function.
D842_I843delinsIM indel gain of function PDGFRA D842_I843delinsIM results in a deletion of two amino acids from aa 842 to 843 within the protein kinase domain of the Pdgfra protein, combined with the insertion of an isoleucine (I) and a methionine (M) at the same site (UniProt.org). D842_I843delinsIM confers a gain of function on the Pdgfra protein as indicated by increased ligand-independent phosphorylation of Pdgfra in cell culture (PMID: 15928335, PMID: 22745105).
D842Y missense gain of function PDGFRA D842Y lies within the protein kinase domain of the Pdgfra protein (UniProt.org). D842Y confers a gain of function on the Pdgfra protein as indicated by increased ligand-independent phosphorylation of Pdgfra in culture (PMID: 15928335, PMID: 22745105).
D846Y missense gain of function PDGFRA D846Y lies within the protein kinase domain of the Pdgfra protein (UniProt.org). D846Y confers a gain of function on the Pdgfra protein as indicated by increased ligand-independent phosphorylation of Pdgfra in cell culture (PMID: 15928335, PMID: 22745105).
H845_N848delinsP indel gain of function PDGFRA H845_N848delinsP results in a deletion of four amino acids from aa 845 to 848 within the protein kinase domain of the Pdgfra protein, combined with the insertion of a proline (P) at the same site (UniProt.org). H845_N848delinsP confers a gain of function on the Pdgfra protein as indicated by increased ligand-independent phosphorylation of Pdgfra in cell culture (PMID: 12522257, PMID: 15928335, PMID: 22745105).
I843_D846del deletion gain of function - predicted PDGFRA I843_D846del results in the deletion of four amino acids in the protein kinase domain of the Pdgfra protein from amino acids 843 to 846 (PMID: 15928335). I843_D846del (identical in amino acid sequence to D842_H845del) is predicted to confer a gain of function to the Pdgfra protein as demonstrated by ligand-independent phosphorylation of Pdgfra (PMID: 12522257).
I843_M844del deletion gain of function - predicted PDGFRA I843_M844del results in the deletion of two amino acids in the protein kinase domain of the Pdgfra protein between amino acids 843 to 844 (UniProt.org). I843_M844del has not been characterized, however, similar PDGFRA exon 18 deletions are activating (PMID: 15928335, PMID: 14645423) and therefore, is predicted to result in a gain of function.
M844_S847del deletion gain of function - predicted PDGFRA M844_S847del results in the deletion of four amino acids within the protein kinase domain of the Pdgfra protein from amino acids 844 to 847 (UniProt.org). M844_S847del has been identified in sequencing studies (PMID: 18547963, PMID: 20470368), but has not been biochemically characterized, however, similar PDGFRA exon 18 deletions are activating (PMID: 12522257, PMID: 15928335) and therefore, is predicted to result in a gain of function.
N659K missense gain of function PDGFRA N659K lies within the protein kinase domain of the Pdgfra protein (UniProt.org). N659K confers a gain of function on the Pdgfra protein as indicated by increased ligand-independent phosphorylation of Pdgfra in cell culture (PMID: 15928335, PMID: 22745105).
N848K missense gain of function PDGFRA N848K lies within the protein kinase domain of the Pdgfra protein (UniProt.org). N848K confers a gain of function on the Pdgfra protein as indicated by increased ligand-independent phosphorylation of Pdgfra in cell culture (PMID: 15928335, PMID: 22745105).
R841_D842delinsKI indel gain of function - predicted PDGFRA R841_D842delinsKI results in a deletion of two amino acids from aa 841 to 842 within the protein kinase domain of the Pdgfra protein, combined with the insertion of a lysine (K) and an isoleucine (I) at the same site (UniProt.org). R841_D842delinsKI is predicted to confer a gain of function on the Pdgfra protein as demonstrated by constitutive phosphorylation of Pdgfra in cell culture (PMID: 15928335).
S566_E571delinsR indel gain of function PDGFRA S566_E571delinsR results in a deletion of six amino acids from aa 566 to 571 within the cytoplasmic domain of the Pdgfra protein, combined with the insertion of an arginine (R) at the same site (UniProt.org). S566_E571delinsR confers a gain of function on the Pdgfra protein as demonstrated by increased ligand-independent phosphorylation of Pdgfra in cell culture (PMID: 12522257, PMID: 15928335).
V561_I562insER insertion gain of function PDGFRA V561_I562insER results in the insertion of two amino acids in the cytoplasmic domain of the Pdgfra protein between amino acids 561 and 562 (UniProt.org). V561_I562insER confers a gain of function on the Pdgfra protein as demonstrated by increased ligand-independent phosphorylation of Pdgfra in cell culture (PMID: 12522257, PMID: 15928335).
Y849C missense gain of function - predicted PDGFRA Y849C lies within the protein kinase domain of the Pdgfra protein (UniProt.org). Y849C is predicted to confer a gain of function on the Pdgfra protein as demonstrated by constitutive phosphorylation of Pdgfra in cell culture (PMID: 15928335).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PDGFRA V561D Advanced Solid Tumor sensitive Imatinib Preclinical Actionable In a preclinical study, cells expressing PDGFRA V561D demonstrated sensitivity to Gleevec (imatinib) in cell culture (PMID: 15928335). 15928335
PDGFRA D842V Advanced Solid Tumor resistant Imatinib Preclinical Actionable In a preclinical study, expression of PDGFRA D842V conferred resistance to Gleevec (imatinib) in cell culture (PMID: 15928335). 15928335