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PDGFRA

Official Full Name
platelet derived growth factor receptor alpha
Organism
Homo sapiens
Gene ID
5156
Background
This gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. Studies suggest that this gene plays a role in organ development, wound healing, and tumor progression. Mutations in this gene have been associated with idiopathic hypereosinophilic syndrome, somatic and familial gastrointestinal stromal tumors, and a variety of other cancers. [provided by RefSeq, Mar 2012]
Synonyms
CD140A; PDGFR2; PDGFR-2
Bio Chemical Class
Kinase
Protein Sequence
MGTSHPAFLVLGCLLTGLSLILCQLSLPSILPNENEKVVQLNSSFSLRCFGESEVSWQYPMSEEESSDVEIRNEENNSGLFVTVLEVSSASAAHTGLYTCYYNHTQTEENELEGRHIYIYVPDPDVAFVPLGMTDYLVIVEDDDSAIIPCRTTDPETPVTLHNSEGVVPASYDSRQGFNGTFTVGPYICEATVKGKKFQTIPFNVYALKATSELDLEMEALKTVYKSGETIVVTCAVFNNEVVDLQWTYPGEVKGKGITMLEEIKVPSIKLVYTLTVPEATVKDSGDYECAARQATREVKEMKKVTISVHEKGFIEIKPTFSQLEAVNLHEVKHFVVEVRAYPPPRISWLKNNLTLIENLTEITTDVEKIQEIRYRSKLKLIRAKEEDSGHYTIVAQNEDAVKSYTFELLTQVPSSILDLVDDHHGSTGGQTVRCTAEGTPLPDIEWMICKDIKKCNNETSWTILANNVSNIITEIHSRDRSTVEGRVTFAKVEETIAVRCLAKNLLGAENRELKLVAPTLRSELTVAAAVLVLLVIVIISLIVLVVIWKQKPRYEIRWRVIESISPDGHEYIYVDPMQLPYDSRWEFPRDGLVLGRVLGSGAFGKVVEGTAYGLSRSQPVMKVAVKMLKPTARSSEKQALMSELKIMTHLGPHLNIVNLLGACTKSGPIYIITEYCFYGDLVNYLHKNRDSFLSHHPEKPKKELDIFGLNPADESTRSYVILSFENNGDYMDMKQADTTQYVPMLERKEVSKYSDIQRSLYDRPASYKKKSMLDSEVKNLLSDDNSEGLTLLDLLSFTYQVARGMEFLASKNCVHRDLAARNVLLAQGKIVKICDFGLARDIMHDSNYVSKGSTFLPVKWMAPESIFDNLYTTLSDVWSYGILLWEIFSLGGTPYPGMMVDSTFYNKIKSGYRMAKPDHATSEVYEIMVKCWNSEPEKRPSFYHLSEIVENLLPGQYKKSYEKIHLDFLKSDHPAVARMRVDSDNAYIGVTYKNEEDKLKDWEGGLDEQRLSADSGYIIPLPDIDPVPEEEDLGKRNRHSSQTSEESAIETGSSSSTFIKREDETIEDIDMMDDIGIDSSDLVEDSFL
Open
Disease
Acute myeloid leukaemia, BCR-ABL1-negative chronic myeloid leukaemia, Brain cancer, Breast cancer, Colon cancer, Colorectal cancer, Gastrointestinal stromal tumour, Gram-positive bacterial infection, Kaposi sarcoma, Lung cancer, Malignant digestive organ neoplasm, Mastocytosis, Multiple myeloma, Myelodysplastic syndrome, Pancreatic cancer, Prostate cancer, Solid tumour/cancer, Stomach cancer, Thrombocytopenia
Approved Drug
4 +
Clinical Trial Drug
6 +
Discontinued Drug
4 +

Cat.No. Product Name Price
SHH372684 shRNA set against Human PDGFRA (NM_006206.4) Inquiry
SHH372688 shRNA set against Mouse PDGFRA (NM_011058.2) Inquiry
SHH372692 shRNA set against Rat PDGFRA (NM_012802.1) Inquiry
SHR101382 shRNA set against Mouse Pdgfra(NM_011058.2) Inquiry
SHR101475 shRNA set against Mouse Pdgfra(NM_001083316.1) Inquiry
SHW005257 shRNA set against Chicken PDGFRA (NM_204749) Inquiry
SHW014913 shRNA set against Danio rerio PDGFRA (NM_131459) Inquiry
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MiUTR1M-09064 PDGFRA miRNA 3'UTR clone Inquiry
MiUTR1M-09065 PDGFRA miRNA 3'UTR clone Inquiry
MiUTR3H-01778 PDGFRA miRNA 3'UTR clone Inquiry
CDCB166732 Chicken PDGFRA ORF Clone (NM_204749) Inquiry
CDCB176388 Danio rerio PDGFRA ORF Clone (NM_131459) Inquiry
CDCB191902 Rabbit PDGFRA ORF clone (XM_008248799.1) Inquiry
CDCR235220 Mouse Pdgfra ORF Clone(NM_001083316.1) Inquiry
CDCR250032 Mouse Pdgfra ORF Clone(NM_011058.2) Inquiry
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Detailed Information

The PDGFRA gene, located on chromosome 4q12, encodes the Platelet-Derived Growth Factor Receptor Alpha (PDGFRA), a member of the type III receptor tyrosine kinase family. The encoded protein consists of 1,089 amino acids. It features an extracellular ligand-binding domain (recognizing homodimers and heterodimers such as PDGF-AA, -BB, -CC), a transmembrane domain, and an intracellular tyrosine kinase domain divided into TK1 and TK2 subdomains. Upon ligand binding, receptor dimerization is induced, triggering autophosphorylation of the TK domain and activating three core downstream pathways:

  • PI3K-AKT pathway: Promotes cell survival and metabolic regulation.
  • RAS-MAPK/ERK pathway: Drives cell proliferation and differentiation.
  • STAT1/3/5 pathway: Regulates gene transcription and inflammatory responses.

PDGFRA activation is ligand-specific: PDGF-AA exclusively activates PDGFRA homodimers, whereas PDGF-BB can activate PDGFRA homodimers, PDGFRB homodimers, or PDGFRA/PDGFRB heterodimers. This versatility allows PDGFRA to respond to diverse microenvironmental cues, contributing to embryonic development and tissue repair.

Pathogenic Mechanisms and Disease Associations

1. Driver Gene in Gastrointestinal Stromal Tumors (GISTs)

Approximately 10% of GISTs are driven by PDGFRA mutations, which are mutually exclusive with KIT mutations. Mutation hotspots are located in three key regions:

  • Exon 12 (near-membrane region of the TK1 domain): Accounts for ~30% of PDGFRA mutations, often involving deletion/insertion mutations such as p.V561_D572delinsR, which result in constitutive kinase activation.
  • Exon 14 (ATP-binding site in TK1 domain): Rare (<1%), with mutations such as p.N659K.
  • Exon 18 (activation loop of the TK2 domain): Accounts for ~70% of mutations, with p.D842V substitutions making up over 80%. This mutation disrupts autoinhibitory structures, leading to ligand-independent kinase activation.

Clinicopathological analyses reveal that PDGFRA-mutant GISTs are predominantly gastric (85%), primarily spindle cell type (80%), with mitotic index ≤5/50 HPF in 75% of cases. However, 37.5% are still classified as high-risk based on NIH criteria. Notably, the D842V mutation shows no significant difference in recurrence-free survival (RFS) or overall survival (OS) compared to wild-type patients but represents a primary resistance mutation that heavily impacts treatment strategies.

2. Molecular Marker of Inflammatory Fibroid Polyps (IFPs)

A 2024 study found PDGFRA mutations in 60.7% of gastrointestinal IFPs, with mutation types closely associated with anatomical location:

  • Gastric IFPs: 80% carry exon 18 mutations, primarily D842V.
  • Small intestinal IFPs: 100% carry exon 12 mutations, such as p.Ser566_Glu571delinsArg.

This anatomical-location-dependent mutation pattern suggests differential dependence on PDGFRA signaling across stromal cell populations. Mutant IFPs also show increased eosinophilic infiltration (average 60±49/HPF) and are significantly associated with polyps larger than 2 cm.

Targeted Therapy and Resistance Mechanisms

The D842V mutation is a primary resistance marker conferring complete resistance to first-generation TKI imatinib (IC50 > 10,000 nM), as it hinders drug binding to the ATP-binding pocket of the kinase. Recent breakthroughs have led to the development of next-generation inhibitors:

  • Avapritinib: Selectively targets the PDGFRA D842V mutant conformation. The phase III VOYAGER trial reported an objective response rate (ORR) of 86% in D842V-mutant GISTs, with a median progression-free survival (PFS) of 34.0 months, 2.7 times longer than with regorafenib.
  • Ripretinib: A dual PDGFRA/KIT inhibitor, showing an ORR of 38% against D842V and the ability to cross the blood-brain barrier, making it suitable for metastatic lesions.

Resistance remains a challenge: approximately 20% of patients treated with avapritinib develop secondary gatekeeper mutations (e.g., p.V658A), which activate compensatory MEK signaling. Combination strategies, such as avapritinib plus MEK inhibitors, have demonstrated synergistic effects in preclinical models.

Future Directions

  • Liquid Biopsy Technologies: ctDNA-based detection of PDGFRA mutation variant allele frequency (VAF) can predict recurrence up to four months earlier than imaging.
  • Immunomicroenvironment Remodeling: D842V-mutant GISTs exhibit high tumor mutational burden and CD8+ T cell infiltration. A phase II trial of PD-1 inhibitors combined with avapritinib is underway (NCT04882138).
  • Germline Mutation Screening: The identification of familial GIST syndrome associated with the PDGFRA p.V561D variant supports the role of genetic counseling in affected families.

References:

  1. Cicala CM, Olivares-Rivas I, Aguirre-Carrillo JA, et al. KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem. Expert Opin Investig Drugs. 2024 Mar;33(3):159-170.
  2. Joensuu H. KIT and PDGFRA Variants and the Survival of Patients with Gastrointestinal Stromal Tumor Treated with Adjuvant Imatinib. Cancers (Basel). 2023 Jul 30;15(15):3879.
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