# Functional interrogation of epigenetic vulnerabilities in KRAS-mutant pancreatic cancer

> **NIH NIH K08** · DANA-FARBER CANCER INST · 2021 · $177,120

## Abstract

Project Summary / Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease and currently the fourth-leading cause of
cancer-related death in the United States. KRAS is mutated in the majority of PDAC and is the major
oncogenic driver of this disease. Unfortunately, attempts to develop drugs that target mutant RAS proteins
have been unsuccessful, and single agent inhibition of effector pathways downstream of mutant KRAS, such
as the RAF-MEK-ERK or PI3K pathways, has also proven ineffective to date. There is a critical unmet need for
novel therapeutic strategies. The overarching goal of this proposal is to utilize functional genetic approaches to
identify novel vulnerabilities and therapeutic strategies in KRAS-mutant PDAC. We have optimized CRISPR-
Cas9 genome-scale negative-selection screening in human PDAC cell lines. Given that inhibition of the RAS-
mitogen-activated-protein-kinase (MAPK) signaling cascade will be an important backbone for combination
therapy approaches in PDAC, we have combined genome-scale CRISPR-Cas9 screening with small molecule
inhibition the MEK1/2 or ERK1/2 kinases to identify novel synthetic lethal targets that demonstrate greater
dependency in the presence of MAPK inhibition. These targets include a many epigenetic regulators, such as
members of the MEN1/MLL1 and PRC2 complexes, as well as numerous transcription factors. Additionally, our
preliminary studies using integrative epigenetic and transcriptional profiling of PDAC cell lines upon disruption
of KRAS signaling suggest that KRAS mediates epigenetic reprogramming that leads to a distinct cell state
with potentially targetable vulnerabilities. This proposal builds on these preliminary data with a specific focus
on: 1) genetic and pharmacologic validation of MEN1 and MLL1 as synthetic lethal targets in combination with
MAPK-inhibition, 2) integrative analysis of epigenetic, transcriptional and functional genetic profiling to
understand the key vulnerabilities unveiled in response to MAPK pathway inhibition in PDAC. Functional
validation and mechanistic understanding of these targets may lead to novel combination therapy strategies in
PDAC patients. Dr. Andrew Aguirre is mentored by Dr. William Hahn, a physician-scientist and expert in
functional cancer genetics, and will also benefit from an advisory committee comprised of Dr. Matthew
Meyerson, Dr. Ramesh Shivdasani and Dr. Brian Wolpin, who will collectively provide mentorship,
collaboration and expertise in cancer biology, epigenetics and pancreatic cancer translational research. Dr.
Aguirre has also formulated a 5-year training plan that will leverage the outstanding resources available at
DFCI and Harvard Medical School, including didactic coursework, scientific meetings and professional
development opportunities that will assist him in achieving his scientific and career goals of developing an
independent pancreatic cancer research laboratory.

## Key facts

- **NIH application ID:** 10221636
- **Project number:** 5K08CA218420-05
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Andrew James Aguirre
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $177,120
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10221636

## Citation

> US National Institutes of Health, RePORTER application 10221636, Functional interrogation of epigenetic vulnerabilities in KRAS-mutant pancreatic cancer (5K08CA218420-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10221636. Licensed CC0.

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