The mitochondrial translation machinery as a therapeutic target in Myc-driven lymphomas

// Aleco D’Andrea 1 , Ilaria Gritti 1,4 , Paola Nicoli 1 , Marco Giorgio 1 , Mirko Doni 1 , Annalisa Conti 2 , Valerio Bianchi 2,5 , Lucia Casoli 2 , Arianna Sabò 2 , Alexandre Mironov 3 , Galina V. Beznoussenko 3 and Bruno Amati 1,2 1 Department of Experimental Oncology, European Institute of Oncology, Milan, Italy 2 Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy 3 The Institute of Molecular Oncology of the Italian Foundation for Cancer Research, Milan, Italy 4 Present address: IRCCS San Raffaele, Functional Genomics of Cancer Unit, Division of Experimental Oncology, Milan, Italy 5 Present address: Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan, Utrecht, The Netherlands Correspondence to: Bruno Amati, email: // Keywords : lymphoma, mitochondria, mitochondrial translation, Myc, Tigecycline Received : June 20, 2016 Accepted : August 25, 2016 Published : August 31, 2016 Abstract The oncogenic transcription factor Myc is required for the progression and maintenance of diverse tumors. This has led to the concept that Myc itself, Myc-activated gene products, or associated biological processes might constitute prime targets for cancer therapy. Here, we present an in vivo reverse-genetic screen targeting a set of 241 Myc-activated mRNAs in mouse B-cell lymphomas, unraveling a critical role for the mitochondrial ribosomal protein (MRP) Ptcd3 in tumor maintenance. Other MRP-coding genes were also up regulated in Myc-induced lymphoma, pointing to a coordinate activation of the mitochondrial translation machinery. Inhibition of mitochondrial translation with the antibiotic Tigecycline was synthetic-lethal with Myc activation, impaired respiratory activity and tumor cell survival in vitro , and significantly extended lifespan in lymphoma-bearing mice. We have thus identified a novel Myc-induced metabolic dependency that can be targeted by common antibiotics, opening new therapeutic perspectives in Myc-overexpressing tumors.