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Abstract 3427: Finding critical cancer driving and cancer suppressing genes using functional genomics screeningin vivo

P53 is one of the most potent tumour suppressors and its activity is also required for cancer cells to respond to diverse chemotherapeutic drugs. Focused functional genetic screens in haematopoietic cells in vivo revealed DNA repair to be one of the most critical downstream pathways for p539s tumour suppressive function. Recently, we extended our search for novel tumour suppressor genes acting potentially outside the p53 tumour suppressor pathway. To this end, we performed whole genome CRISPR/Cas9 knockout screening in vivo, using the Eµ-Myc transgenic mouse model. This identified previously unknown genes and hence pathways, which upon deletion/mutation lead to the acceleration of tumour onset. Amongst these novel tumour suppressor genes, we identified the GATOR1 members DEPDC5 and NPRL3, which are known inhibitors of the mTOR pathway. Interestingly, drug mediated inhibition of mTOR activity with rapamycin or Torin1 in GATOR1 deficient Eµ-Myc cells led to efficient killing of these malignant cells, which was in striking contrast to control Eµ-Myc lymphoma cells that were resistant to this treatment. In parallel we conducted CRISPR/Cas9 screens for identifying p53 bound promoter and enhancer elements in haematopoietic cells in vivo. Excitingly, we observed that targeting the NPRL3 promoter led to accelerated tumour onset in the Eµ-Myc transgenic model, suggesting that NPRL3 is under direct transcriptional control of p53. These results indicate that p53 mediated shutdown of the mTOR pathway through upregulation of the GATOR1 member NPRL3 is a critical tumour suppressive function of p53. Citation Format: Marco Josef Herold, Shinsuke Mizutani, Yexuan Deng, Ana Janic, Andrew Kueh, Martin Pal, Stephen Wilcox, Lin Tai, Gemma L. Kelly, Andreas Strasser. Finding critical cancer driving and cancer suppressing genes using functional genomics screening in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3427.