# Dual Kinase and LSD1 Inhibition in Acute Myeloid Leukemia

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $488,445

## Abstract

PROJECT SUMMARY/ABSTRACT
Kinase inhibitor therapy has made a minimal impact on the clinical treatment of patients with Acute Myeloid
Leukemia (AML). We have shown that inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1)
augments the efficacy of kinase inhibition in AML, including drugs targeting FLT3, cKIT and JAK2. This occurs
via the repression of the MYC super enhancer (MYC-SE), leading to a loss of MYC gene expression and
consequently decreased expression of a pro-proliferative gene expression program. However, we lack a
complete mechanistic understating of how kinase plus LSD1 inhibition produces this effect, or whether the drug
combination has important effects that are independent from the MYC-SE. Our long-term objective is to establish
the efficacy of kinase plus LSD1 inhibition in AML, translating this concept into new effective treatment for
patients with AML. The overall objective of this proposal is to: 1) define the mechanistic basis for drug responses
to FLT3 plus LSD1 inhibition in FLT3-mutant AML and 2) evaluate the potential of dual MEK and LSD1 inhibition
in NRAS-mutant AML. Our central hypothesis is that the suppression of MYC-target genes is an essential
mechanism of kinase plus LSD1 inhibition-mediated cell death. In Aim 1, we will investigate three possible
mechanisms for FLT3 plus LSD1 inhibition-induced suppression of MYC target genes: 1) Via inactivation of the
MYC-SE leading to decreased MYC gene expression resulting in a loss of MYC-target gene expression, 2) Via
inhibition of LSD1-dependent activation of MYC-target genes and 3) through inhibition of signaling pathways
down-stream of activated FLT3, resulting in a loss of MYC binding to the promoters of target genes. We will also
perform correlative studies investigating these mechanisms in AML patients enrolled in the FRIDA trial, receiving
FLT3 plus LSD1-inhbitor therapy. In Aim 2, we will evaluate the efficacy and mechanism of action of MEK plus
LSD1 inhibitor therapy in NRAS-mutant AML, using an integrated evaluation of chromatin and signaling pathway
dynamics. We will also employ multiple mouse models of NRAS-mutant AML including a patient-derived
xenograft model. At the completion of these studies, our expected outcomes are to 1) have identified how FLT3
plus LSD1 inhibition drives cell death in FLT3-mutant AML and 2) establish the preclinical efficacy of dual MEK
plus LSD1 inhibition in NRAS-mutant AML. These studies will provide key pre-clinical rationale for expanding
the indications for kinase plus LSD1 inhibitor to a larger proportion of patients with AML.

## Key facts

- **NIH application ID:** 10887555
- **Project number:** 5R01CA282133-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Theodore Paul Braun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $488,445
- **Award type:** 5
- **Project period:** 2023-07-13 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887555

## Citation

> US National Institutes of Health, RePORTER application 10887555, Dual Kinase and LSD1 Inhibition in Acute Myeloid Leukemia (5R01CA282133-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10887555. Licensed CC0.

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