RIOK1 kinase activity is required for cell survival irrespective of MTAP status

// Alexandra Hormann 1, * , Barbara Hopfgartner 1, * , Thomas Kocher 2 , Maja Corcokovic 1 , Teresa Krammer 1 , Christoph Reiser 1 , Gerd Bader 1 , Junwei Shi 3 , Katharina Ehrenhofer 1 , Simon Wohrle 1 , Norbert Schweifer 1 , Christopher R. Vakoc 3 , Norbert Kraut 1 , Mark Pearson 1 , Mark Petronczki 1 and Ralph A. Neumuller 1 1 Boehringer Ingelheim RCV GmbH & Co KG, 1120 Vienna, Austria 2 Vienna Biocenter Core Facilities GmbH, 1030 Vienna, Austria 3 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA * These authors have contributed equally to this work Correspondence to: Ralph A. Neumuller, email: ralph.neumueller@boehringer-ingelheim.com Keywords: RIOK1; MTAP; PRMT5; cancer; target Received: November 16, 2017     Accepted: May 19, 2018     Published: June 19, 2018 ABSTRACT Genotype specific vulnerabilities of cancer cells constitute a promising strategy for the development of new therapeutics. Deletions of non-essential genes in tumors can generate unique vulnerabilities which could be exploited therapeutically. The MTAP gene is recurrently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A . Recent studies have uncovered an increased dependency of MTAP -deleted cancer cells on the function of a PRMT5 containing complex, including WDR77, PRMT5 and the kinase RIOK1. As RIOK1 kinase activity constitutes a potential therapeutic target, we wanted to test if MTAP deletion confers increased sensitivity to RIOK1 inhibition. Using CRISPR/Cas9-mediated genome engineering we generated analog sensitive alleles of RIOK1 in isogenic cell lines differing only by MTAP status. While we were able to independently confirm an increased dependency of MTAP -deleted cells on PRMT5, we did not detect a differential requirement for RIOK1 kinase activity between MTAP -proficient and deficient cells. Our results reveal that the kinase activity of RIOK1 is required for the survival of cancer cell lines irrespective of their MTAP status and cast doubt on the therapeutic exploitability of RIOK1 in the context of MTAP -deleted cancers.