PDGFRA – Gastrointestinal Stromal Tumor

Platelet‐derived growth factor receptor alpha (PDGFRA) is a receptor tyrosine kinase that is mutated in a subset of gastrointestinal stromal tumors (GISTs), representing an alternative oncogenic driver to KIT. Somatic heterozygous activating mutations in PDGFRA occur in approximately 5–7% of GISTs, predominantly in KIT‐wild‐type cases (PMID:12522257). These mutations cluster in the juxtamembrane domain (exon 12) and activation loop (exon 18), altering kinase conformation and downstream signaling.

Genetic studies of 1,105 GISTs identified PDGFRA mutations in 66 cases (6.0%), with 55% affecting codon 842 (D842V) and the remainder involving codons 561, 659, and 846–848 (PMID:15928335). The most recurrent variant is c.2525A>T (p.Asp842Val), which confers primary resistance to imatinib. Non‐D842V exon 18 mutations (e.g., p.Asn659Lys) and exon 12 variants (e.g., p.Val561Asp) remain sensitive to imatinib, yielding partial responses in vitro and in patients.

Functional assays demonstrate that PDGFRA D842V and V561D mutants induce ligand‐independent autophosphorylation and Ba/F3 cell proliferation. The V561D mutant is inhibited by imatinib (IC₅₀ ≈ 0.3 µM), whereas D842V is refractory (IC₅₀ > 10 µM), owing to stabilization of the active “DFG‐in” conformation and increased ATP affinity (PMID:12949711; PMID:17087936). Alternative inhibitors such as PKC412 and avapritinib show potent activity against D842V in preclinical models.

Clinical outcome data from 58 patients with advanced PDGFRA‐mutant GISTs treated with imatinib reveal a 0% response rate for D842V substitutions versus 68% response for other exon 18 mutations; median progression‐free survival was 2.8 months for D842V and 28.5 months for non‐D842V cases (PMID:22718859). This underscores the importance of mutational profiling in guiding TKI therapy.

Conflicting evidence is limited. Rare familial PDGFRA germline mutations (e.g., p.Val561Asp) cause predisposition to GIST and mastocytosis but do not alter the overarching somatic association. No large cohorts have reported refuting the oncogenic role of PDGFRA in GIST.

In summary, activating PDGFRA mutations define a distinct molecular subgroup of GIST with characteristic morphology, variable TKI sensitivity, and clear implications for diagnostic mutation screening and personalized therapy. Key take-home: PDGFRA mutational status is a clinically actionable biomarker in GIST.

References

• Science • 2003 • PDGFRA activating mutations in gastrointestinal stromal tumors PMID:12522257
• Gastroenterology • 2003 • Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors PMID:12949711
• Journal of Clinical Oncology • 2005 • PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib PMID:15928335
• Clinical Cancer Research • 2012 • Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era PMID:22718859

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