# Targeting Malic Enzyme 3 as a Synthetic Lethality Target in Pancreatic Cancer

> **NIH NIH R00** · ROSWELL PARK CANCER INSTITUTE CORP · 2021 · $249,000

## Abstract

Project Summary/Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common cancer of the pancreas and 5-year survival
rate for PDAC patients is a dreadful ~6%. PDAC genome sustains frequent deletion of tumor suppressor gene
loci, most notably SMAD4, which is homozygously deleted in approximately 30% of cases. As loss of
neighboring housekeeping genes can confer collateral lethality, I sought to determine whether loss of the
metabolic gene malic enzyme (ME) 2 in the SMAD4 locus would create a cancer-specific metabolic
vulnerability upon targeting its paralogous isoform ME3. Using in vitro and in vivo model system, I
demonstrated that ME3 depletion in ME2 null PDAC cells causes cell death. Mechanistically, integrated
metabolomic and molecular investigation of mitochondrial ME-deficient cells revealed diminished NADPH
production and consequent high ROS which activates AMP activated protein kinase (AMPK), and which in turn
suppresses BCAT2 (Branched chain amino acid transaminase 2) gene via sterol regulatory element-binding
protein 1 (SREBP1)-directed transcription. BCAT2 catalyzes the transfer of the amino group from branched
chain amino acids (BCAA) to alpha-ketoglutarate (αKG) thereby regenerating glutamate, which functions in
part to support de novo nucleobase synthesis. In summary, this data shows that mitochondrial ME is required
for pancreatic cancer survival and can be exploited as vulnerability for treatment. The goal of the project is to
determine the druggability of ME in PDAC. In order to achieve this goal, I propose the following: 1) Systematic
validation of Malic Enzyme as a therapeutic target in pancreatic cancer, 2) Mechanistic understanding of
metabolic deregulation upon ME3 extinction; 3) Identification of selective ME3 inhibitors. By addressing the
above aim, I will gain further insights into the structural features of ME3 and generate a blueprint for rational
drug design to target ME3. Moreover, I will also identify the potential resistance or metabolic bypass
mechanism of ME3 treatment by tracing metabolites such as BCAA and glutamine. Moreover, my unique
understanding of the BCAA regulation will identify new avenues for targeting surrogate target of ME3. Finally,
will undertake structure-function analysis of ME3 and validate the top hits identified by in-silico analysis.

## Key facts

- **NIH application ID:** 10241331
- **Project number:** 5R00CA218891-05
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Prasenjit Dey
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241331

## Citation

> US National Institutes of Health, RePORTER application 10241331, Targeting Malic Enzyme 3 as a Synthetic Lethality Target in Pancreatic Cancer (5R00CA218891-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241331. Licensed CC0.

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