Paralog Dependency May Be Exploitable in Tumors Lacking Chromosome 1p

An emerging concept borne out of synthetic lethality screens is that inactivation of particular genes can confer dependency on their functionally redundant paralogs. Viswanathan and colleagues analyzed such dependencies in genome-wide shRNA and CRISPR synthetic lethal screen datasets and identified the paralogs MAGOH and MAGOHB as genes for which dependency was significantly correlated with inactivation of its paralog. Of note, MAGOH is located on chromosome 1p, which is commonly deleted in human tumors, and hemizygous MAGOH loss occurs in 21% of all tumors cataloged in The Cancer Genome Atlas. MAGOHB was the top dependency in cells with hemizygous MAGOH loss, and chromosome 1p deletion status correlated with MAGOHB dependency. MAGOH and MAGOHB encode core components of the exon–junction complex, a multisubunit complex that acts at exon–exon junctions during splicing and facilitates targeting of transcripts with premature termination codons for nonsense-mediated decay (NMD). In MAGOH-deleted cells, decreased viability upon MAGOHB knockdown was associated with increased intron retention and expression of transcripts that typically would undergo NMD. MAGOHB does not have domains that are obviously amenable to targeting by small molecules, but delivery of MAGOHB siRNA with tumor-penetrating nanocomplexes suppressed growth of tumors with hemizygous deletion of MAGOH. A search for potentially more tractable dependencies that correlated with either MAGOH or MAGOHB dependency identified IPO13, a gene also located on chromosome 1p that encodes the karyopherin responsible for importing MAGOH and MAGOHB to the nucleus, as the top correlated gene dependency to both MAGOH and MAGOHB. Delivery of IPO13 siRNA also suppressed growth of tumors with hemizygous deletion of MAGOH, suggesting that indirect inhibition of MAGOHB may also be effective in the setting of MAGOH loss. Overall, these findings raise the possibility that MAGOH–MAGOHB paralog lethality and the MAGOHB–IPO13 axis may be exploitable vulnerabilities in a substantial subset of human tumors.

Viswanathan SR, Nogueira MF, Buss CG, Krill-Burger JM, Wawer MJ, Malolepsza E, et al. Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer. Nat Genet 2018;50:937–43.

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