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Cancers 2019, 11(1), 121;

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

Department of Neurosurgery, Toho University Ohashi Medical Center, Tokyo 153-8515, Japan
Author to whom correspondence should be addressed.
Received: 16 December 2018 / Revised: 11 January 2019 / Accepted: 19 January 2019 / Published: 20 January 2019
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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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). View Full-Text
Keywords: NOTCH; glioma initiating cell; PTEN; PI3K pathway; glioblastoma NOTCH; glioma initiating cell; PTEN; PI3K pathway; glioblastoma

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Saito, N.; Hirai, N.; Aoki, K.; Suzuki, R.; Fujita, S.; Nakayama, H.; Hayashi, M.; Ito, K.; Sakurai, T.; Iwabuchi, S. The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma. Cancers 2019, 11, 121.

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