The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma.

ABSTRACT: The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH activity. Here we report loss of PTEN function as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of oncogene addiction from the NOTCH pathway to the PI3K pathway. Drug cytotoxicity testing of eight GICs showed a differential growth response to GSI, and the GICs were thus stratified into two groups: sensitive and resistant. In the sensitive group, GICs with loss of PTEN function appeared less sensitive to GSI treatment. Here we show that NOTCH regulates PTEN expression and the activity of

SUBMITTER: Saito N 

PROVIDER: S-EPMC6356490 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature