Effects of PI3K and MEK inhibitors in mutated PIK3CA gliomas

Undergraduates: Shrey Patel, Madison K. Butler Robert S. McNeill, Erin Smithberger

Faculty Advisor: Robert McNeill
Department: Chemistry

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Glioblastoma (GBM) is the most common and lethal malignant brain tumor. The phosphoinositide 3-kinase (PI3K) pathway is frequently mutated in GBM and its activation can promote tumorigenesis in preclinical models. PI3K is a heterodimeric kinase composed of both regulatory (PIK3R1) and catalytic (PIK3CA) subunits. Pathway activation occurs via phosphorylation of PIP2 to PIP3 by the catalytic subunit. We previously found that missense mutations in PIK3CA activate PI3K signaling and promote tumorigenesis in immortalized human astrocytes (NHA) and NHA with mutant RAS. Preclinical models suggested AKT activation in the mutated PI3K pathway along with MAPK signaling promoted tumorigenesis. However, PIK3CA mutations have not been studied in relation to gliomagenesis. Pathway inhibition with the PI3K inhibitor buparlisib (BKM120) and the MEK inhibitor selumetinib (AZD6244) was investigated at different concentrations as well as together. BKM120 inhibited proximal (pAKT) and distal (pS6) PI3K signaling while increasing MAPK (pERK) signaling independent of PIK3CA or mutant RAS status. AZD6244 inhibited MAPK in NHA and NHARAS lines independent of the presence of PIK3CA mutations. Moreover, AZD6244 increased pAKT in all NHA lines, however, pAKT was only increased in NHARAS lines lacking PIK3CA mutations. Treatment with both drugs in combination inhibited both the PI3K and MAPK signaling suggesting dual treatment would be more effective than either drug alone.