# The novel PRMT5-substrate adaptor interface provides a therapeutic target in MTAP null tumors

> **NIH NIH F32** · BROAD INSTITUTE, INC. · 2020 · $67,446

## Abstract

Project Abstract
 Pancreatic cancer is one of the most lethal types of cancer worldwide. Less than 7% of patients survive
this deadly disease. Despite efforts, few effective therapies exist. Intriguingly, the methyltransferase PRMT5 has
been identified as a cancer dependency in MTAP null tumors, which constitute 15% of all tumors and 30% of
pancreatic ductal adenocarcinomas. Therefore, PRMT5 is an attractive target in pancreatic cancer. This PRMT5
dependency arises due to the passenger deletion of the MTAP gene that is adjacent to the frequently deleted
tumor suppressor gene CDKN2A on chromosome 9. In tumors lacking MTAP, its substrate, methylthioadenosine
(MTA) accumulates and competitively inhibits the PRMT5 enzyme.!While therapeutic targeting of PRMT5 has
focused on targeting the catalytic pocket, our preliminary studies demonstrate a novel and potentially important
face of the PRMT5 methylosome that may overcome cellular specificity and efficacy issues with PRMT5 catalytic
inhibitors. Therefore, I hypothesize that the newly identified PRMT5-substrate adaptor interface is required for
PRMT5 activity and is thus essential for the growth of MTAP null tumors. Through the following two Aims, we
will address whether the PRMT5-substrate adaptor site is required for all or particular PRMT5 functions and
establish whether disruption of this protein interaction site might have a therapeutic benefit in pancreatic cancer.

## Key facts

- **NIH application ID:** 9968184
- **Project number:** 5F32CA232543-03
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Kathleen Mulvaney
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968184

## Citation

> US National Institutes of Health, RePORTER application 9968184, The novel PRMT5-substrate adaptor interface provides a therapeutic target in MTAP null tumors (5F32CA232543-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9968184. Licensed CC0.

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