One of the most common genetic alterations in glioblastoma (30-40%) occurs in the tumor suppressor gene PTEN (phosphatase and tensin homolog), where loss of function has been mechanistically linked to increased tumor cell invasion, and to a lack of radio- and chemo-therapy response. To identify new drug compounds that target PTEN-deficient brain tumors we performed a high throughput drug screening using patient-derived GBM spheres and found that PTEN-deficient samples were highly sensitive to proteasome inhibitors. We confirmed PTEN dependency to proteasome inhibition by genetically overexpressing or deleting PTEN in GBM cells and established that the drug inhibition response relied on PTEN enzymatic activity. Additionally, proteasome inhibition specifically suppressed tumor growth and increased survival of mice orthotopically engrafted with human PTEN-null glioblastoma cancer stem cells. Mechanistically, we determined that PTEN-deficient cells were more sensitive to proteasome inhibition due to an increase in protein synthesis rate and loss of autophagy activity associated with activation of the PI3K/mTOR pathway. Finally, integrated in silico analysis of the Samsung Medical Center dataset corroborated that samples with PTEN/EGFR/PI3K alterations were significantly more sensitive to Carfilzomib, an FDA-approved proteasome inhibitor. This study reveals that PTEN-deficient cells are "proteasome addictive" and opens a new therapeutic opportunity to treat glioblastoma PTEN-deficient patients.

Citation Format: Jorge A. Benitez, Darren Finlay, Alexandre Rosa-Campos, Jianhui Ma, Tomoyuki Koga, Kristiina Vuori, Frank Furnari. Proteasome addiction a new therapeutic opportunity to treat PTEN-deficient brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-110.