# Kinase-independent mechanism of resistance to FLT3 inhibitors in AML

> **NIH NIH K08** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $262,179

## Abstract

Project Summary/Abstract
Somatic FMS-like tyrosine kinase 3 (FLT3) mutations are associated with a poor prognosis and
increased rates of relapse in acute myeloid leukemia (AML). There is evolving evidence describing
genetic-dependent mechanisms of resistance in FLT3-mutant AML following targeted therapy with
FLT3 inhibitors, including the phenylalanine 691 to leucine (F691L) mutation that has been reported in
patients treated with current generation of FLT3 inhibitors. While AML cells containing this mutation
experience inhibition of kinase activity and canonical FLT3 signaling following exposure to FLT3i
treatment, our preliminary data revealed that FLT3-F691L AML cells continued propagating leukemia
both in vitro and in vivo. The perplexing finding that kinase activity canonical FLT3 signaling is
suppressed, despite ongoing survival of the AML cells, suggested kinase independent signaling
resulting from F691L substitution in FLT3. The long-term goal of this project is understanding the
mechanism of resistance underlying the FLT3-F691L mutation, which we believe is not fully explained
by gatekeeper functionality solely. The specific aims for this project are: (i) determine the effects of
kinase-dependent and -independent signaling in FLT3-ITD and FLT3- F691L AML cells on
differentiation, survival, and gene expression, (ii) identify the pathways and molecules mediating
kinase-independent signaling in FLT3-F691L AML, and (iii) examine novel therapeutic vulnerabilities for
FLT3-F691L AML and evaluate prioritized pharmacologic combination therapy to overcome resistance.
The impact of this grant application is highly significant, as it will have translational implications, filling
an unmet need for relapsed/refractory FLT3 mutant AML. If this mechanism of resistance holds true,
this could inform drug development and combinatorial therapies for various pediatric cancer types in the
long-term.

## Key facts

- **NIH application ID:** 10813146
- **Project number:** 5K08CA270305-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** LaQuita M Jones
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $262,179
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813146

## Citation

> US National Institutes of Health, RePORTER application 10813146, Kinase-independent mechanism of resistance to FLT3 inhibitors in AML (5K08CA270305-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10813146. Licensed CC0.

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