The Role of PIK3CA Mutations in Driving Gliomagenesis (2015)

Undergraduates: Emily Stroobant, Robbie McNeill

Faculty Advisor: C. Ryan Miller
Department: Chemistry

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Glioblastoma (GBM) is the most aggressive form of brain cancer, and is currently incurable. Major treatment advances have not been made for a decade. Molecular diagnostics will potentially enable patients to be stratified according to their mutation status, to direct treatment and improve patient outcomes. Successful implementation of precision medicine will be aided by preclinical investigations of the role of individual mutations in tumorigenesis and their response to targeted drugs. Mutations in PIK3CA, the p110¿¿ subunit of phosphatidylinositide 3-kinase (PI3K), are highly implicated cancer pathogenesis, and drugs targeting PI3K are in clinical development. PIK3CA is mutated in 12% of GBM, and recurrent mutations are distributed across three functional domains (adaptor binding, helical, and kinase). However, their role in GBM tumorigenesis is unknown. We examined six mutations known to occur in GBM, two per mutated domain, for activation of biochemical signaling pathways, as well as for response to PI3K inhibitors. These mutations were introduced into immortalized human astrocytes, with and without oncogenic RAS. The downstream signaling molecule AKT is activated by all of the mutations in human astrocytes, with the greatest increase from mutations in the helical and kinase domains. The presence of oncogenic RAS increases the ability of mutations to activate signaling. Preliminary data shows that treatment with the pan-PI3K inhibitor BKM120 inhibited PI3K signaling.