Abstract LB-115: TPRKB dependency in p53-deficient cancers

Abstract

Abstract TP53 (p53) is an extensively studied tumor suppressor mutated in approximately 50% of all cancers. Identification of vulnerabilities imposed by p53 alterations may enable effective targeted therapy development. Thus, this study aimed to identify and characterize novel vulnerabilities in this context. Through analyzing shRNA screening data from the Broad Institute’s Project Achilles, we identified TPRKB, a poorly characterized member of the tRNA-modifying EKC/KEOPS complex, as the most significant vulnerability in p53 mutated cancer cell lines. In vitro, across multiple benign-immortalized and cancer cell lines, we confirmed that TPRKB knockdown in p53-deficient cells significantly inhibited proliferation, while there was little to no effect in p53 wild-type cells. Furthermore, p53 reintroduction into TPRKB-sensitive p53-null cells resulted in loss of TPRKB sensitivity, confirming the importance of p53 status in this context. To determine whether this response was unique to TPRKB or a result of impairment of the EKC/KEOPS complex, we knocked down other members of the complex: PRPK, OSGEP, and LAGE3. PRPK loss showed minor changes between p53 wild type versus deficient cells; while OSGEP and LAGE3 loss resulted in a significant decrease regardless of p53 status. For the first time, we have demonstrated a potential role for TPRKB in cancer, and our results suggest that effects of TPRKB knockdown in p53-deficient cancer cells may be independent of its role in the EKC/KEOPS complex. Citation Format: Kelly VanDenBerg, Moloy Goswami, Lei Lucy Wang, Bhavneet Singh, Travis Weiss, Sumin Han, Dan Rhodes, Felix Feng, Scott Tomlins. TPRKB dependency in p53-deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-115. doi:10.1158/1538-7445.AM2017-LB-115