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 the PI3K pathway in GICs, as treatment with GSI attenuated the NOTCH pathway and increased PTEN expression. NOTCH regulates PTEN expression via Hes-1, as knockdown of Notch or Hes1 increased expression of PTEN. This novel observation suggests that both pathways must be simultaneously inhibited in order to improve therapeutic efficacy in human glioblastomas (GBMs).
Highlights
IntroductionGenetic heterogeneity between patients and even within tumors is high, and GBM is characterized by evolving genetic aberration resulting from dynamic genetic instability
Glioblastoma (GBM), the most common adult glioma, has a poor prognosis
GSIs showed a dose-dependent inhibition of glioma initiating cells (GICs) of GICs and glioma cell lines
Summary
Genetic heterogeneity between patients and even within tumors is high, and GBM is characterized by evolving genetic aberration resulting from dynamic genetic instability. By combining sequencing data with other types of genomic information, the Cancer Genome Atlas team produced a tentative overview of the main biological pathways involved in GBM. Each of the three pathways (namely, the CDK/RB, p53 and RTK/RAS/PI3K pathways) was disrupted in more than three-quarters of GBM tumors. Signal transduction pathways are complex and exhibit overlap and crosstalk [2]. The complexity of these pathways may allow for compensatory effects in alternative pathways, which could lead to resistance to single agents that regulate only one target. Successful novel therapeutic strategies for GBMs may require simultaneous targeting of multiple dysregulated molecules
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