THE ROLES OF PI3K AND MAPK PATHWAY MUTATIONS IN GLIOMAGENESIS AND RESPONSE TO TARGETED INHIBITION

Abstract

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, and even with treatment, its median survival is only 12-15 months. Molecular analyses by The Cancer Genome Atlas and others have identified the genetics underlying GBM pathogenesis, but this knowledge has yet to influence therapy. The receptor tyrosine kinase (RTK) pathway is frequently mutated in GBM, including its phosphoinositide-3-kinase (PI3K) and mitogen activated protein kinase (MAPK) effector arms. Because of their mutational frequency and established role in GBM pathogenesis, these pathways are important therapeutic targets. However, results from clinical investigations of inhibitors targeting RTK/PI3K/MAPK signaling in GBM have been disappointing. The primary aim of this dissertation was to determine how PI3K and MAPK pathway mutations influence response to targeted inhibition. We previously developed a series of non-germline genetically engineered mouse (nGEM) models in which PI3K and/or MAPK signaling were activated in immortalized astrocytes (T) by deletion of Pten (P) and expression of a constitutively active Kras mutant (R), respectively. We used these models to define how PI3K/MAPK mutations and drug potency influence signaling dynamics, efficacy, and synergism of PI3K and MEK inhibitors. We found that PI3K/MAPK signaling are alternate bypass pathways that promote resistance to inhibition of either pathway alone. Pten/Kras mutation status and drug potency interacted to influence single agent efficacy and PI3K/MEK inhibitor synergism. Subcutaneous TRP allografts were most sensitive to dual PI3K/MEK inhibitor treatment, but target inhibition and efficacy were limited in orthotopic allografts. PIK3CA missense mutations frequently occur in GBM, but their role in disease pathogenesis had not been experimentally validated. We therefore transduced immortalized, normal human astrocytes with lentiviral vectors encoding wild-type or mutant PIK3CA. We showed that mutations in the helical or kinase domains of PIK3CA activate PI3K signaling and cooperate with mutant RAS to potentiate gliomagenesis in orthotopic xenografts. PIK3CA mutations did not affect PI3K inhibitor efficacy, but they influenced synergism with MEK inhibition. Taken together, the work described here explored how PI3K and MAPK mutations altered response to targeted inhibition, and will inform future research into predictive biomarkers and rationale combination therapies.Doctor of Philosoph