CSIG-41. ONCOGENE ADDICTION SWITCH FROM NOTCH TO PI3K REQUIRE SIMULTANEOUS TARGETING OF DUAL PATHWAY INHIBITION IN GLIOBLASTOMA. (5th November 2018)

• Record Type: Journal Article
• Authors: Saito, Norihiko; Aoki, Kazuya; Hirai, Nozomi; Suzuki, Ryo; Fujita, Satoshi; Nakayama, Haruo; Hayashi, Morito; Sakurai, Takatoshi; Iwabuchi, Satoshi
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi52
• Page End: vi52
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.207
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Notch signaling pathway regulates normal stem cells in the brain and glioma stem cells (GSCs). However, blocking the proteolytic activation of NOTCH with γ-secretase inhibitors (GSIs) fails to alter the growth of some GSCs as GSIs seem to be active in only a fraction of GSCs lines with constitutive NOTCH activity. Here we report loss of PTEN as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of "oncogene addiction" from the NOTCH to the phosphoinositol-3 kinase (PI3K) pathway. We investigated the effects of Notch inhibition in GSC using GSI. Drug cytotoxicity test on 16 GSCs show differential growth response to GSI stratifying GSCs into two groups: responders vs non-responders. Active Notch signaling seems to be important features for the GSC as Notch inhibition only affected GSCs defined as having increased Notch activity. However in the responder group GSCs with the PTEN mutation seems to be less sensitive to GSI treatment. Here we show that NOTCH regulates the expression of PTEN and the activity of the PI3K signaling pathway in GSCs since treatment with GSI attenuated Notch signaling and increases PTEN expression. NOTCH regulates PTEN expression via Hes-1 as knockdown of either Notch or Hes1 led to increase expression of PTEN.This novel observation suggests the need to simultaneous inhibition of both pathways as a means to improve therapeutic efficacy in human glioblastoma.