title: Large-scale analysis of PDGFRA mutations in melanomas and evaluation of their sensitivity to tyrosine kinase inhibitors imatinib and crenolanib.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Authors' Affiliations: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China; and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jie
authors.initials: J
authors.lastname: Dai
authors.forename: Yan
authors.initials: Y
authors.lastname: Kong
authors.forename: Lu
authors.initials: L
authors.lastname: Si
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Chi
authors.forename: Chuanliang
authors.initials: C
authors.lastname: Cui
authors.forename: Xinan
authors.initials: X
authors.lastname: Sheng
authors.forename: Lili
authors.initials: L
authors.lastname: Mao
authors.forename: Siming
authors.initials: S
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Lian
authors.forename: Ruifeng
authors.initials: R
authors.lastname: Yang
authors.forename: Shujing
authors.initials: S
authors.lastname: Liu
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides / Q000008:administration & dosage*; D001562:Benzimidazoles / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
chemical_list: D001549:Benzamides; D001562:Benzimidazoles; D010879:Piperazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; C577197:crenolanib