The Role of PIK3CA Mutations in Proliferation and Migration of Immortalized Human Astrocytes (2015)

Undergraduates: Demitra Canoutas, Emily Stroobant Robert McNeill C. Ryan Miller

Faculty Advisor: Ryan Miller
Department: Biology

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Glioblastoma (GBM), grade IV astrocytoma, is incurable and has minimally efficacious therapeutic options. The PI3K effector arm of the receptor tyrosine kinase pathway has an established role in cancer and is frequently mutated in GBM. One gene in this pathway that is often mutated is PIK3CA, which encodes the catalytic subunit of PI3K. Missense mutations in this oncogene are heterogeneously distributed across three functional domains (adaptor binding, helical, and kinase), but their role in GBM tumorigenesis and response to targeted inhibitors has not been experimentally determined. In order to define the effects of PIK3CA missense mutations on gliomagenesis and efficacy of PI3K inhibitors, we overexpressed two mutations per mutated domain in immortalized normal human astrocytes (NHA), either with or without oncogenic RAS. The presence of PIK3CA mutations increased proliferation of NHA in low serum culture in the absence of oncogenic RAS, but their effects were minimal in its presence. Moreover, these mutations increased migration across a wound in NHA with and without oncogenic RAS. Whether the presence of PIK3CA mutations influence the response to treatment with a PI3K inhibitor is as yet unknown, but will be determined in the future.