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

Hörmann, A., Hopfgartner, B., Köcher, T., Corcokovic, M., Krammer, T., Reiser, C., Bader, G., Shi, J., Ehrenhöfer, K., Wöhrle, S., Schweifer, N., Vakoc, C. R., Kraut, N., Pearson, M., Petronczki, M., Neumüller, R. A. (June 2018) RIOK1 kinase activity is required for cell survival irrespective of MTAP status. Oncotarget, 9 (47). pp. 28625-28637. ISSN 1949-2553

DOI: 10.18632/oncotarget.25586


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.

Item Type: Paper
Additional Information: 1949-2553 Hörmann, Alexandra Hopfgartner, Barbara Köcher, Thomas Corcokovic, Maja Krammer, Teresa Reiser, Christoph Bader, Gerd Shi, Junwei Ehrenhöfer, Katharina Wöhrle, Simon Schweifer, Norbert Vakoc, Christopher R Kraut, Norbert Pearson, Mark Petronczki, Mark Neumüller, Ralph A P01 CA013106/CA/NCI NIH HHS/United States R01 CA174793/CA/NCI NIH HHS/United States R01 GM045436/GM/NIGMS NIH HHS/United States Journal Article Oncotarget. 2018 Jun 19;9(47):28625-28637. doi: 10.18632/oncotarget.25586. eCollection 2018 Jun 19.
Uncontrolled Keywords: Mtap Prmt5 Riok1 cancer target
Subjects: diseases & disorders > cancer
Investigative techniques and equipment > CRISPR-Cas9
diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
CSHL Authors:
Communities: CSHL labs > Vakoc lab
CSHL Cancer Center Program > Cancer Genetics and Genomics Program
Depositing User: Matthew Dunn
Date: 19 June 2018
Date Deposited: 10 Dec 2020 21:25
Last Modified: 07 Jun 2021 16:02
PMCID: PMC6033344
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