ABSTRACT: Viswanathan SR, Nogueira MF, Buss CG, Krill-Burger JM, Wawer MJ, Malolepsza E, Choi PS, Berger A, Shih J, Tanenbaum B, Strathdee CA, Tamayo P, Pedamallu CS, Vazquez F, Lage K, Carr SA, Schenone M, Bhatia SN, Cherniack AD, Tsherniak A, Hahn WC, Meyerson M. Nature Genetics 2018. Chromosome arm-level deletion events are highly prevalent across cancer types. The targeting of functionally redundant paralog genes required for cell viability has been proposed as a potential therapeutic strategy to selectively kill cancer cells with chromosome arm deletions. Here, we identify MAGOHB as a novel therapeutic target for chromosome 1p deleted cancer through an analysis of paralog dependencies emerging from genome-wide shRNA screening of cancer cell lines. MAGOHB and its functionally redundant paralog, MAGOH, are core members of the exon-junction complex (EJC), a multi-protein complex that is deposited at exon-exon junctions after mRNA splicing and that has important roles in regulating pre-mRNA splicing, mRNA transport, and nonsense-mediated decay (NMD) MAGOHB is the top differential dependency in cells with hemizygous loss of MAGOH, a pervasive passenger genetic event across multiple tumor types that frequently occurs in the context of chromosome 1p loss. Inhibition of MAGOHB in cells with deletion of MAGOH compromises viability by globally perturbing alternative splicing and RNA surveillance, resulting in an accumulation of premature-termination codon-containing transcripts. We further identify IPO13, a bidirectional karyopherin that mediates nuclear import of the MAGOH/B-Y14 heterodimer as a potentially druggable target whose dependency is highly correlated to both MAGOH and MAGOHB dependency, suggesting a rationale for inhibiting MAGOH/MAGOHB function by interfering with EJC recycling. Finally, we validate MAGOHB as a target in vivo through delivery of a tumor-penetrating peptide-siRNA nanocomplex. Our results define MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and identify the MAGOHB-IPO13 axis as an potential therapeutic target in MAGOH-deleted cancers and in cancers with chromosome 1p deletion.
Steven A. Carr 
