Reference Detail

Ref Type Journal Article
PMID (22745105)
Authors Heinrich MC, Griffith D, McKinley A, Patterson J, Presnell A, Ramachandran A, Debiec-Rychter M
Title Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 18
Issue 16
Date 2012 Aug 15
URL
Abstract Text To determine the potential of crenolanib, a potent inhibitor of PDGFRA, to treat malignancies driven by mutant PDGFRA.The biochemical activity of crenolanib was compared with imatinib using a panel of PDGFRA-mutant kinases expressed in several different cell line models, including primary gastrointestinal stromal tumors (GIST) cells. The antiproliferative activity of crenolanib was also studied in several cell lines with PDGFRA-dependent growth.Crenolanib was significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRA kinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843). For example, crenolanib was 135-fold more potent than imatinib against D842V in our isogenic model system, with an IC(50) of approximately 10 nmol/L. The relative potency of crenolanib was further confirmed in BaF3 and primary GIST cells expressing PDGFRA D842V. In contrast, imatinib was at least 10-fold more potent than crenolanib in inhibiting the V561D mutation. For all other tested PDGFRA mutations, crenolanib and imatinib had comparable potency.Crenolanib is a potent inhibitor of imatinib-resistant PDGFRA kinases associated with GIST, including the PDGFRA D842V mutation found in approximately 5% of GISTs. The spectrum of activity of crenolanib suggests that this drug is a type I inhibitor (inhibitor of activated conformation of kinase). Based in part on these results, a phase II clinical study of this agent to treat GIST with the PDGFRA D842V mutation has been initiated.

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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
Crenolanib Crenolanib 26 5
Drug Name Trade Name Synonyms Drug Classes Drug Description
Crenolanib CP-868596 FLT3 Inhibitor 50 PDGFR Inhibitor (Pan) 27 Crenolanib is a type III receptor tyrosine kinase inhibitor of PDGFR-alpha/beta and FLT3, which results in inhibition of downstream signaling and prevents growth in tumor cells (PMID: 22745105).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
D842_H845del deletion gain of function PDGFRA D842_H845del results in the deletion of four amino acids in the protein kinase domain of the Pdgfra protein from amino acids 842 to 845 (UniProt.org). D842_H845del confers a gain of function on the Pdgfra protein as indicated by increased ligand-independent phosphorylation of Pdgfra in cell culture (PMID: 22745105, PMID: 12522257).
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).
D842I missense gain of function - predicted PDGFRA D842I lies within the protein kinase domain of the Pdgfra protein (UniProt.org). D842I is predicted to confer a gain of function to the Pdgfra protein as indicated by increased ligand-independent phosphorylation of Pdgfra (PMID: 22745105).
D842V missense gain of function PDGFRA D842V lies within the protein kinase domain of the Pdgfra protein (UniProt.org). D842V results in ligand-independent phosphorylation of Pdgfra, activation of downstream signaling, and is transforming in culture (PMID: 22745105, PMID: 23752188, PMID: 29533785). Y
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).
I843del deletion gain of function PDGFRA I843del results in the deletion of one amino acid in the protein kinase domain of the Pdgfra protein (UniProt.org). I843del confers a gain of function on the Pdgfra protein as indicated by increased ligand-independent phosphorylation of Pdgfra in cell culture (PMID: 22745105, PMID: 14645423).
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).
R560_V561insER insertion gain of function - predicted PDGFRA R560_V561insER results in the insertion of two amino acids in the cytoplasmic domain of the Pdgfra protein between amino acids 560 and 561 (UniProt.org). R560_V561insER is predicted to confer a gain of function on the Pdgfra protein as indicated by increased ligand-independent phosphorylation of Pdgfra in cell culture (PMID: 22745105).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PDGFRA N659K Advanced Solid Tumor sensitive Crenolanib Preclinical Actionable In a preclinical study, crenolanib decreased Pdgfra phosphorylation in cells expressing PDGFRA N659K in culture (PMID: 22745105). 22745105
PDGFRA N659K Advanced Solid Tumor sensitive Imatinib Preclinical Actionable In a preclinical study, Gleevec (imatinib) decreased Pdgfra phosphorylation in cells expressing PDGFRA N659K in culture (PMID: 22745105). 22745105
PDGFRA D842V Advanced Solid Tumor sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib inhibited Pdgfra phosphorylation and proliferation of transformed cells expressing PDGFRA D842V in culture (PMID: 22745105). 22745105