Abstract 3933: RRM2 inhibition by COH29 is a potential therapeutic strategy for atypical teratoid rhabdoid tumors

Abstract

Abstract Introduction: Atypical teratoid rhabdoid tumors (ATRT) are a rare but aggressive malignancy in central nervous system, commonly occurring in early childhood. ATRT patients face a dismal prognosis despite aggressive therapy. Development of both effective and protective targeted therapy is an emerging necessity. It has been reported that RRM2 is a master driver of aggressiveness and a poor prognosis biomarker in several cancers. However, little is known about RRM2 function in ATRT. The aim of this study is to assess the roles of RRM2 in ATRT and elucidate the therapeutic potential of RRM2 to cure the ATRT. Methods: Expression of RRM2 was evaluated by molecular profiling analysis and was confirmed by IHC in both ATRT patients and PDX tissues. Follow-up in vitro studies used 3 different cell lines to elucidate the oncogenic role of RRM2 in ATRT cells. The efficacy of COH29, an RRM2 inhibitor, was assessed in vitro. ATRT model of SCID mice orthotopically injected with ATRT cells were used to test the efficiency of COH29 for in vivo. Western blot and RNA-sequencing were used to determine the mechanisms of RRM2 transcriptional activation in ATRT. Results: Molecular profiling results revealed that RRM2 was relatively highly expressed in ATRT tissues and cell lines. Clinical relevance analysis results showed that the RRM2 expression level was associated with poor prognosis among ATRT patients. Knockdown of RRM2 by shRNAs significantly reduced ATRT cells colonies formation, proliferation and migration. A similar but more pronounced inhibitory effect was observed when COH29 was used to target RMM2. Inhibition of RRM2 by shRNAs or COH29 significantly induced cell death via DNA damage and/or apoptosis pathways. In vivo results demonstrated that COH29 could suppressed ATRT tumor growth and extend mice overall survival. Conclusion: Our study identified RRM2 as a potential mediator of oncogenic cellular functions in ATRT cell lines. We propose that highly expressed RRM2 is associated with poor patient outcomes, and inhibition of RRM2 by COH29 may present a significant therapeutic value in ATRT. Citation Format: Le Hien Giang, Tai-Tong Wong, Che- Chang. RRM2 inhibition by COH29 is a potential therapeutic strategy for atypical teratoid rhabdoid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3933.