Reference Detail

Ref Type Journal Article
PMID (24132921)
Authors Dai J, Kong Y, Si L, Chi Z, Cui C, Sheng X, Mao L, Li S, Lian B, Yang R, Liu S, Xu X, Guo J
Title Large-scale analysis of PDGFRA mutations in melanomas and evaluation of their sensitivity to tyrosine kinase inhibitors imatinib and crenolanib.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 19
Issue 24
Date 2013 Dec 15
URL
Abstract Text Platelet-derived growth factor receptor α (PDGFRA) is a target for tyrosine kinase inhibitor (TKI)-based targeted therapy. Dysregulation of PDGFRA has been reported in many cancers. However, PDGFRA mutations in melanomas have not been well studied. We analyzed the genetic mutations of PDGFRA in Chinese patients with melanoma and determined the inhibitory potency of TKIs, such as imatinib and crenolanib, on mutant PDGFRA.Of note, 351 melanoma tissue samples were examined for genetic mutations in exons 12, 14, and 18 of PDGFRA. Activities of mutations in response to imatinib and crenolanib were analyzed by Western blotting of tyrosine-phosphorylated PDGFRA and cell proliferation assays.PDGFRA mutations were observed in 4.6% (16 of 351) of melanomas, and these mutations were mainly detected in acral and mucosal melanomas. PDGFRA mutations seem to be mutually exclusive with KIT mutations, but may coexist with BRAF and NRAS mutations. The genetic mutations of PDGFRA were unrelated to the age, thickness, and ulceration status of primary melanomas. Thirteen mutations were not reported before, and five (P577S, V658A, R841K, H845Y, and G853D) of them resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except that V658A mutation was imatinib-resistant, all the other mutations were sensitive to both imatinib and crenolanib.PDGFRA mutations are detected in a small population of melanoma patients. Our study suggests that patients with melanoma harboring certain PDGFRA mutations may benefit from imatinib and crenolanib treatment.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
G853D missense gain of function - predicted PDGFRA G853D lies within the protein kinase domain of the Pdgfra protein (UniProt.org). G853D is predicted to confer a gain of function to the Pdgfra protein, as indicated by increased autophosphorylation of Pdgfra (PMID: 24132921).
H845Y missense gain of function PDGFRA H845Y lies within the tyrosine kinase 2 domain of the Pdgfra protein (PMID: 24132921). H845Y results in increased Pdgfra autophosphorylation and is transforming in cell culture (PMID: 24132921).
P577S missense gain of function - predicted PDGFRA P577S lies within the juxtamembrane domain of the Pdgfra protein (PMID: 24132921). P577S is predicted to confer a gain of function to the Pdgfra protein as demonstrated by increased autophosphorylation of Pdgfra (PMID: 24132921).
R554_Y555del deletion unknown PDGFRA R554_Y555del results in the deletion of two amino acids in the juxtamembrane domain of the Pdgfra protein from amino acids 554 to 555 (PMID: 24132921). R554_Y555del has not been characterized and therefore, its effect on Pdgfra protein function is unknown (PubMed, Jul 2018).
R558C missense no effect - predicted PDGFRA R558C lies within the juxtamembrane domain of the Pdgfra protein (PMID: 24132921). R558C has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Pdgfra (PMID: 29533785).
R560_S564del deletion unknown PDGFRA R560_S564del results in the deletion of five amino acids in the juxtamembrane domain of the Pdgfra protein from amino acids 560 to 564 (PMID: 24132921). R560_S564del has not been characterized and therefore, its effect on Pdgfra protein function is unknown (PubMed, Jul 2018).
R841K missense gain of function - predicted PDGFRA R841K lies within the protein kinase domain of the Pdgfra protein (UniProt.org). R841K is predicted to confer a gain of function on the Pdgfra protein as demonstrated by increased autophosphorylation of Pdgfra (PMID: 24132921).
V561A missense gain of function - predicted PDGFRA V561A lies within the cytoplasmic domain of the Pdgfra protein (UniProt.org). V561A is predicted to confer a gain of function on the Pdgfra protein as demonstrated by in increased phosphorylation of Pdgfra in cultured cells (PMID: 24132921).
V658A missense gain of function - predicted PDGFRA V658A lies within the protein kinase domain of the Pdgfra protein (UniProt.org). V658A is predicted to confer a gain of function on the Pdgfra protein as demonstrated by increased autophosphorylation of Pdgfra (PMID: 24132921).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PDGFRA R841K Advanced Solid Tumor sensitive Imatinib Preclinical Actionable In a preclinical study, Gleevec (imatinib) inhibited Pdgfra phosphorylation and decreased proliferation in cells expressing PDGFRA R841K in culture (PMID: 24132921). 24132921
PDGFRA R841K Advanced Solid Tumor sensitive Crenolanib Preclinical Actionable In a preclinical study, crenolanib inhibited Pdgfra phosphorylation and decreased proliferation in cells expressing PDGFRA R841K in culture (PMID: 24132921). 24132921
PDGFRA H845Y Advanced Solid Tumor sensitive Crenolanib Preclinical Actionable In a preclinical study, crenolanib inhibited Pdgfra phosphorylation in cells expressing PDGFRA H845Y in culture (PMID: 24132921). 24132921
PDGFRA V658A Advanced Solid Tumor sensitive Crenolanib Preclinical Actionable In a preclinical study, crenolanib inhibited Pdgfra phosphorylation and decreased proliferation in cells expressing PDGFRA V658A in culture (PMID: 24132921). 24132921
PDGFRA P577S Advanced Solid Tumor sensitive Crenolanib Preclinical Actionable In a preclinical study, crenolanib inhibited Pdgfra phosphorylation and decreased proliferation in cells expressing PDGFRA P577S in culture (PMID: 24132921). 24132921
PDGFRA G853D Advanced Solid Tumor sensitive Imatinib Preclinical Actionable In a preclinical study, Gleevec (imatinib) inhibited Pdgfra phosphorylation and decreased proliferation in transformed human cells expressing PDGFRA G853D in culture (PMID: 24132921). 24132921
PDGFRA D842Y Advanced Solid Tumor sensitive Imatinib Preclinical Actionable In a preclinical study, Gleevec (imatinib) inhibited Pdgfra phosphorylation and decreased proliferation in transformed human cells expressing PDGFRA D842Y in culture (PMID: 24132921). 24132921
PDGFRA D842Y Advanced Solid Tumor sensitive Crenolanib Preclinical Actionable In a preclinical study, Crenolanib inhibited Pdgfra phosphorylation and decreased proliferation in transformed human cells expressing PDGFRA D842Y in culture (PMID: 24132921). 24132921
PDGFRA H845Y Advanced Solid Tumor sensitive Imatinib Preclinical Actionable In a preclinical study, Gleevec (imatinib) inhibited Pdgfra phosphorylation in cells expressing PDGFRA H845Y in culture (PMID: 24132921). 24132921
PDGFRA P577S Advanced Solid Tumor sensitive Imatinib Preclinical Actionable In a preclinical study, Gleevec (imatinib) inhibited Pdgfra phosphorylation and decreased proliferation in cells expressing PDGFRA P577S in culture (PMID: 24132921). 24132921
PDGFRA V658A Advanced Solid Tumor sensitive Imatinib Preclinical Actionable In a preclinical study, crenolanib inhibited Pdgfra phosphorylation and decreased proliferation in transformed human cells expressing PDGFRA V658A in culture (PMID: 24132921). 24132921
PDGFRA G853D Advanced Solid Tumor sensitive Crenolanib Preclinical Actionable In a preclinical study, crenolanib inhibited Pdgfra phosphorylation and decreased proliferation in transformed human cells expressing PDGFRA G853D in culture (PMID: 24132921). 24132921