The Role of PIK3CA Mutations in Gliomagenesis and Response to Kinase Inhibitors

Undergraduates: Madison Butler, Shrey Patel Robert McNeill, Juanita Limas

Faculty Advisor: C. Ryan Miller
Department: Biology

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Glioblastoma (GBM), a grade IV astrocytoma, is the most common malignant primary brain tumor. The receptor tyrosine kinase (RTK) pathway, including its mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) effector arms, is frequently mutated in GBM. Moreover, mutational activation of PI3K and MAPK signaling via Pten/PIK3R1 mutations and constitutively active mutant RAS cooperate to promote gliomagenesis. Mutations in the catalytic subunit of PI3K, PIK3CA, occur across multiple domains in GBM. We previously utilized immortalized normal human astrocytes (NHA) with and without expression of oncogenic RAS to determine that helical and kinase, but not adaptor-binding (ABD), domains of PIK3CA mutations increased PI3K signaling and potentiated gliomagenesis in vitro and in vivo. Because there is extensive cross-talk between PI3K and MAPK pathways, we next tested whether PIK3CA mutations influenced response to PI3K or MEK inhibitors. PI3Ki and MEKi as single agents reduced growth, but activated the alternate pathway. Therefore, we also measured the effects of PI3K and MEK inhibitors in combination. We found that buparlisib and selumetinib were synergistic across all mutations, but most pronounced in cell lines harboring mutations in ABD and helical domains. Therefore, targeted combination therapy in vivo could be effective in treating GBM containing ABD or helical domain PIK3CA mutations.