Schematic diagram of the potential sites in the PI3 kinase pathway where resistance to single-agent TKIs directed against the EGFR might occur. 1) The phosphatase activity of the PTEN gene product is lost in the majority of GBM, favoring accumulation of the triphosphate form of phosphatylinositol, PIP3; 2) Activating mutations in the PIK3CA gene, controlling the catalytic subunit of PI3K are well-documented, also favoring accumulation of PIP3;3) In addition, increased expression of the phospho-AKT enhancer, PIKE-A, is found. These alterations may occur in isolation or in any combination in GBM.
Abbreviations: EGFR, epidermal growth factor receptor; GBM, glioblastoma multiforme; PTEN, phosphatase and tensin homologue deleted on chromosome 10; TKIs, tyrosine kinase inhibitors.