Abstract NG02: NFS1 undergoes positive selection in lung tumors and protects cells from ferroptosis

Abstract

Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality. Here, using RNAi-based loss of function screening, we identify environmental oxygen level as a major driver of differential essentiality between in vitro model systems and in vivo tumours. Above the 3-8% oxygen concentration typical of most tissues, we find that cancer cells depend on high levels of the iron-sulfur cluster (ISC) biosynthetic enzyme NFS1. Accordingly, mammary or subcutaneous tumours grow despite NFS1 suppression, while metastatic or primary lung tumours do not. Consistent with a role in surviving the high oxygen environment of incipient lung tumours, NFS1 lies in a region of genomic amplification present in lung adenocarcinoma and is most highly expressed in well-differentiated adenocarcinomas. NFS1 activity is particularly important for maintaining the ISC cofactors present in multiple cell-essential proteins upon exposure to O2 compared to other forms of oxidative damage. Additionally, insufficient ISC maintenance robustly activates the iron-starvation response and, in combination with glutathione biosynthesis inhibition, triggers ferroptosis, a non-apoptotic form of cell death. Suppression of NFS1 cooperates with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumour growth. Therefore, lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage. These observations lead to the tantalizing hypothesis that one can trick cancer cells into taking up large quantities of iron and releasing intracellular iron stores via modulation of NFS1 or downstream effectors, such as IRPs, leaving them at increased risk for ROS-mediated cell death mechanisms such as ferroptosis. Citation Format: Samantha W. Alvarez, Vladislav O. Sviderskiy, Erdem M. Terzi, Thales Papagiannakopoulos, Andre L. Moreira, Sylvia Adams, David M. Sabatini, Kıvanç Birsoy, Richard L. Possemato. NFS1 undergoes positive selection in lung tumors and protects cells from ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr NG02.