Mutations in PDGFRA, are associated with an array of clinically significant neoplasms, notably ones of the clonal hypereosinophilia class of malignancies, as well as gastrointestinal stromal tumors (GISTs).
The activated receptor phosphorylates itself and other proteins, and thereby engages intracellular signaling pathways that trigger cellular responses such as migration and proliferation.
[5] Non-PDGFs bind to their own receptors that trigger intracellular events that de-repress the kinase activity of PDGFRα monomers.
[10] Mice genetically engineered to express a constitutively (i.e. continuously) activated PDGFRα mutant receptor eventually develop fibrosis in the skin and multiple internal organs.
These mutations create fused genes which encode chimeric proteins that possess continuously active PDGFRA-derived tyrosine kinase.
They thereby continuously stimulate cell growth and proliferation and lead to the development of leukemias, lymphomas, and myelodysplastic syndromes that are commonly associated with hypereosinophilia and therefore regarded as a sub-type of clonal eosinophilia.
[13][14][17][18] Patients afflicted with any one of these translocation mutations, similar to those afflicted with the interstitial PDGFRA-FIP1l1 fusion gene: a) present with findings of chronic eosinophilia, hypereosinophilia, the hypereosinophilic syndrome, or chronic eosinophilic leukemia; myeloproliferative neoplasm/myeloblastic leukemia; a T-lymphoblastic leukemia/lymphoma; or myeloid sarcoma; b) are diagnosed cytogenetically, usually by analyses that detect breakpoints in the short arm of chromosome 4 using Fluorescence in situ hybridization; and c) where treated (many of the translocations are extremely rare and have not be fully tested for drug sensitivity), respond well or are anticipated to respond well to imatinib therapy as described for the treatment of diseases caused by FIP1L1-PDGFRA fusion genes.
[19] A randomized trial testing the efficacy of crenolanib in patients with GIST tumors bearing the D842V mutation is under recruitment.
In addition, the European Medicines Agency granted conditional approval for olaratumab in this indication in November 2016 following a review under the EMA's Accelerated Assessment Program.
[22] Gain-of-function H3K27M mutations in protein histone H3 lead to inactivation of polycomb repressive complex 2 (PRC2) methyltransferase and result in global hypomethylation of H3K27me3 and transcriptional derepression of potential oncogenes.
[23] In a small non-randomized trial study, imatinib therapy in patients with glioblastoma selected on the basis of having imatinib-inhibitable tyrosine kinases in biopsy tissue caused marginal disease improvement compared to similar treatment of patients with unselected recurrent glioblastoma.
This suggests that patient sub-populations with excessive PDGFRA-related or other tyrosine kinase-related over-activity might benefit from imatinib therapy.