Abstract LB-270: Targeting USP1 decreases glioblastoma stem cell survival and tumor growth.

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor. GBM cells are highly resistant to standard-of-care therapies including radiation and chemotherapy, indicating an urgent need for the development of novel therapeutics. Recent evidence suggests that deubiquitinating enzymes are overexpressed or activated in various cancers, and they contribute to tumor progression and recurrence. Here, we report that the deubiquitinating enzyme ubiquitin-specific peptidase 1 (USP1) is highly expressed in GBMs and the targeting USP1 decreases cell survival and tumor growth. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated self-renewal and survival of GSCs. As one of the molecular mechanism that link USP1 to pro-tumorigenic roles, we found that the USP1 stabilized the inhibitor of DNA binding protein1 (ID1) and checkpoint kinase 1 (CHEK1), both of which are positive GSC regulators and implicated in radioresistance. Inhibition of USP1 in GBM cells leads to hypersensitivity to ionizing radiation through the decrease in DNA damage repair capacity. Finally, USP1 inhibition in orthotopic GBM xenografts significantly reduced tumor growth and prolonged the survival of tumor bearing mice. Together, our findings suggest that USP1 is a promising therapeutic target for GBMs and provide a rationale for positioning USP1 inhibitor as a GBM radiosensitizer. Citation Format: Young Taek M. Oh, Eunhee Kim, Jeongwu Lee, Do-Hyun Nam. Targeting USP1 decreases glioblastoma stem cell survival and tumor growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-270. doi:10.1158/1538-7445.AM2013-LB-270