MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells
Open accessAbstract
Tumors put in a vulnerable position: Cancer cells often display alterations in metabolism that help fuel their growth. Such metabolic “rewiring” may also work against the cancer cells, however, by creating new vulnerabilities that can be exploited therapeutically. A variety of human tumors show changes in methionine metabolism caused by loss of the gene coding for 5-methylthioadenosine phosphorylase (MTAP). Mavrakis et al. and Kryukov et al. found that the loss of MTAP renders cancer cell lines sensitive to growth inhibition by compounds that suppress the activity of a specific arginine methyltransferase called PRMT5. Conceivably, drugs that inhibit PRMT5 activity could be developed into a tailored therapy for MTAP-deficient tumors. Science , this issue pp. 1208 and 1214
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MTAP-null cancer cells are more sensitive to PRMT5 depletion than isogenic cancer cells that express MTAP.
“MTAP loss results in reduced PRMT5 activity and renders MTAP-null cancer cell more sensitive to PRMT5 depletion than isogenic counterparts that express MTAP (Kryukov et al., 2016; Marjon et al., 2016; Mavrakis et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Kryukov et al., 2016
Loss of MTAP causes MTA to accumulate, and this MTA can inhibit PRMT5, creating a vulnerability in cancer cells.
“Loss of MTAP expression can result in another vulnerability for cancer cells because the MTA that accumulates following MTAP loss can act as a potent inhibitor of the enzyme arginine methyltransferase 5 (PRMT5).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Kryukov et al., 2016
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- Authors
- Kryukov, G. V., Wilson, F. H., Ruth, J. R., Paulk, J., Tsherniak, A., Marlow, S. E., Vazquez, F., Weir, B. A., Fitzgerald, M. E., Tanaka, M., Bielski, C. M., Scott, J. M., Dennis, C., Cowley, G. S., Boehm, J. S., Root, D. E., Golub, T. R., Clish, C. B., Bradner, J. E., Hahn, W. C., & Garraway, L. A.
- Affiliations
- Broad Institute (US)
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
- Corresponding author
- Kryukov, Gregory V.
- Wilson, Frederick H.
- Ruth, Jason R.
- Garraway, Levi A.
- ORCID
- Venue
- Science
- Published
- 2016-03-11
- Volume
- 351
- Issue
- 6278
- Pages
- 1214-1218
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4997612
- OpenAlex
- W2257573908
- Cited by
- 688
- References
- 33
- Citations by year
- 2026: 107 · 2025: 139 · 2024: 87 · 2023: 62 · 2022: 56 · 2021: 57 · 2020: 38 · 2019: 46 · 2018: 30 · 2017: 39 · 2016: 26
- FWCI
- 24.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Novartis Institutes for BioMedical Research
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Melanoma Research Alliance
- NIH PO1 Research Program
- Integrative Cancer Biology Program (U54 CA112962)
- Conquer Cancer Foundation
- 2014 AACR-Bristol-Myers Squibb Oncology Fellowship in Clinical Cancer Research (14-40-15-WILS)
- arin Grunebaum Cancer Research Foundation
- National Center for Research Resources
- National Center for Advancing Translational Sciences
- NIH (U01 CA176058, KL2 TR001100)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- MTAP deletion, PRMT5, protein arginine methyltransferase, methylthioadenosine, CDKN2A, PRMT5 inhibitors, cancer vulnerability, therapeutic target
- MeSH terms
- Deoxyadenosines, Enzyme Inhibitors, Humans, Isoquinolines, Neoplasms, Protein-Arginine N-Methyltransferases, Purine-Nucleoside Phosphorylase, Pyrimidines, Thionucleosides, Transcription Factors, Gene Deletion, Cell Line, Tumor
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