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MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells
Gregory V Kryukov1, Frederick H Wilson1, Jason R Ruth1
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration.
Insights
Loss of methylthioadenosine phosphorylase (MTAP) creates a cancer vulnerability to PRMT5 inhibition. This discovery offers new therapeutic targets for MTAP-deleted cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Cancer dependencies can guide therapeutic strategies and drug target identification.
- Methylthioadenosine phosphorylase (MTAP) is frequently lost in cancers due to its location near the CDKN2A tumor suppressor gene.
Purpose of the Study:
- To investigate the functional consequences of MTAP loss in cancer.
- To identify potential therapeutic vulnerabilities associated with MTAP deletion.
Main Methods:
- Genomic profiling of cancer cell lines.
- Functional characterization of cancer cell dependencies.
- Measurement of intracellular methylthioadenosine (MTA) levels.
- Assay of PRMT5 enzymatic activity.
- Assessment of cell viability in response to MTA and PRMT5 inhibitors.
Main Results:
- Loss of MTAP leads to a selective dependence on protein arginine methyltransferase 5 (PRMT5) and WDR77.
- MTAP-deleted cells accumulate methylthioadenosine (MTA), which inhibits PRMT5.
- MTA and PRMT5 inhibitors preferentially impair viability in MTAP-null cancer cells.
Conclusions:
- PRMT5 is a potential therapeutic vulnerability in cancers with MTAP deletion.
- The common genomic alteration of MTAP loss creates a targetable dependency on PRMT5.
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