Selenocysteine metabolism is a targetable vulnerability in MYCN-amplified cancers

Understanding the operational molecular, and metabolic networks that determine the balance between pro- and anti-ferroptotic regulatory pathways could unravel unique vulnerabilities to be exploited for cancer therapy. Here we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis in vitro and in orthotopic neuroblastoma mouse models. Specifically, the exquisite dependency on LRP8-mediated selenocysteine import is caused by the failure of MYCN-amplified cells to efficiently utilize alternative forms of selenium/selenocysteine based uptake necessary for selenoprotein biosynthesis. Increased activity of one of such transporters, SLC7A11, in MYCN-amplified cells leads to cysteine overload, progressive mitochondrial decline and impaired proliferation. These data reveal in LRP8 a targetable, and specific vulnerability of MYCN-amplified neuroblastoma cells and disclose a yet-unaccounted mechanism for selective ferroptosis induction that has the potential to become an important therapeutic entry point for MYCN-amplified neuroblastoma. ### Competing Interest Statement Competing interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.C. is the co-founder of ROSCUE THERAPEUTICS GmbH and author of patent application related to ferroptosis. G.S-F. is co-author of patent applications related to SLCs, co-founder of Solgate GmbH as well as the Academic Project Coordinator of the IMI grants RESOLUTE and Resolution in partnership with Pfizer, Novartis, Bayer, Sanofi, Boehringer-Ingelheim and Vifor Pharma. The G.S-F. laboratory receives funds from Pfizer. All other authors declare no other relevant conflicts of interest.