Rearrangements of PDGFRA (including FIP1L1-PDGFRα) is a common abnormality among patients with chronic eosinophilic leukemia. In addition, activating mutations (eg, p.H650Q, p. N659S, p.R748G, p.Y849S) in PDGFRA have been reported in FIP1L1-PDGFRα-negative chronic eosinophilic leukemia and resistance mutations in PDGFRA (eg. p.D842V, p.T674I) have been reported in the setting of imatinib therapy for patients with FIP1L1-PDGFRα. These PDGFRA mutations have variable responses to the different available tyrosine kinase inhibitors.

The D842V mutation results in an amino acid substitution at position 842 in PDGFRA, from an aspartic acid (D) to a valine (V). This mutation occurs within the TK2 domain. PDGFRA D842V mutation has been found in a distinct subset of GIST, typically from the stomach. The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance. Recent evidence has shown that Dasatinib has been also recently associated with promising clinical activity in patients with advanced GIST carrying exon 18 mutation of the PDGFRA gene (including the D842V mutation). Interestingly, recent in vitro data have suggested that crenolanib, a highly selective and potent inhibitor of both PDGFRA and PDGFRB, blocks phosphorylation of D842V mutant PDGFRA at clinically achievable concentrations

PDGFRA amplification is reportedly present in up to 29% of pediatric and 21% of adult high-grade astrocytomas when assessed by flourescent in situ hydridization. Copy number alterations of this gene have been repoted in approximately 11% of adult glioblastoma making it the second most commonly altered receptor tyrosine kinase after EGFR. In those adult glioblastomas that are IDH-mutant, there is evidence to suggest that amplification of PDGFRA is associated with worse overall survival.

This gene is a known cancer gene.

This gene is a known cancer gene.

PDGFRA amplification is reportedly present in up to 29% of pediatric and 21% of adult high-grade astrocytomas when assessed by flourescent in situ hydridization. Copy number alterations of this gene have been reported in approximately 11% of adult glioblastoma making it the second most commonly altered receptor tyrosine kinase after EGFR. In those adult glioblastomas that are IDH-mutant, there is evidence to suggest that amplification of PDGFRA is associated with worse overall survival. Somatic mutations within the PDGFRA gene are less frequent than amplifications. PGDFRA N659K is within the tyrosine kinase domain and confers a gain of function. Preclinical trials in N659K mutant cell lines have shown sensitivity to multi-targeted tyrosine kinase inhibitors including imatinib and crenolanib.