# RNA Polymerase II as a Therapeutic Target in Acute Myeloid Leukemia (AML) with RAS Signaling Activation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $550,626

## Abstract

PROJECT SUMMARY/ABSTRACT
Background: Fms-Like Tyrosine Kinase 3 (FLT3) is the most commonly mutated gene in acute
myeloid leukemia (AML) and mutations in FLT3 are associated with high relapse rates. FLT3
tyrosine kinase inhibitors (TKIs) are clinically active in FLT3-mutant AML but duration of
response is limited by the development of resistance. Mutations in NRAS and other activation
of the RAS pathway are major mechanisms of resistance to FLT3 inhibitors and other AML
targeted therapies. Rationale: We have identified suppression of the Mediator/RNA Pol II
pathway augments FLT3 TKI-induced apoptosis in the setting of RAS activation. The overall
goals of this project are: (1) to prioritize therapeutic targets in the Mediator/RNA Pol II pathway;
and (2) to determine the essential Mediator/RNA Pol II-dependent transcriptional targets
relevant to FLT3 TKI resistance. Methods: We will identify essential components of the RNA Pol
II pathway needed for TKI resistance in AML and evaluate the efficacy of existing RNA Pol II
pathway inhibitors in MAPK-activated AML cells. We will determine RNA Pol II-dependent
transcriptional changes induced by MAPK activation and FLT3 inhibition in pre-clinical models
and patient samples. We will functionally validate the essential downstream transcriptional
targets critical to RAS-mediated FLT3 TKI resistance in AML. Expected Results: These studies
will rigorously evaluate RNA Pol II as a novel treatment strategy in AML with aberrant
RAS/MAPK signaling. If successful, this strategy can be quickly translated to clinical trials in
AML and this general approach may also prove efficacious in other RAS-mutant cancers.

## Key facts

- **NIH application ID:** 10520647
- **Project number:** 1R01CA266422-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Catherine Choy Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $550,626
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520647

## Citation

> US National Institutes of Health, RePORTER application 10520647, RNA Polymerase II as a Therapeutic Target in Acute Myeloid Leukemia (AML) with RAS Signaling Activation (1R01CA266422-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10520647. Licensed CC0.

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