MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells
Broad Institute · Harvard University · +1 more institution
Abstract
The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore,…
Citation impact
- FWCI
- 25.59
- Percentile
- 100%
- References
- 33
Authors
21- GVGregory V. KryukovCorresponding
Broad Institute, Harvard University, Dana-Farber Cancer Institute
- FHFrederick H. WilsonCorresponding
Broad Institute, Harvard University, Dana-Farber Cancer Institute
- JRJason R. RuthCorresponding
Broad Institute, Harvard University, Dana-Farber Cancer Institute
- JPJoshiawa Paulk
Broad Institute, Harvard University, Dana-Farber Cancer Institute
- ATAviad Tsherniak
Broad Institute
Topics & keywords
- Protein arginine methyltransferase 5
- Arginine
- Methyltransferase
- Dependency (UML)
- Chemistry
- Cancer
- Biochemistry
- Cancer research
Funding
- CCConquer Cancer Foundation
- MRMelanoma Research Alliance
- DMDr. Miriam and Sheldon G. Adelson Medical Research Foundation
- NINational Institutes of HealthAwards: KL2 TR001100, U01 CA176058
- NINovartis Institutes for BioMedical Research
- NCNational Center for Research Resources
- NCNational Center for Advancing Translational Sciences