# Negative MAPK-RAS-ERK pathway regulation to sustain CIC-DUX4 expression

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $75,236

## Abstract

Project Summary/Abstract
Transcription factor (TF) fusion genes create oncoproteins that drive tumorigenesis. While TF fusions
represent cancer specific alterations, direct therapeutic targeting remains a clinical challenge. One
example is the CIC-DUX4 TF fusion which defines an aggressive subset of round cell sarcoma in
children and young adults. The clinical outcomes for CIC-DUX4 patients remain dismal due to high
metastatic propensity and ineffective therapies. Currently, no therapies exist that direclty target the CIC-
DUX4 fusion. To meet this need, we have recently identified a mechanistic link between the terminal
MAPK signaling substrate, ERK, and CIC-DUX4. Specifically, ERK physically binds and phosphorylates
CIC-DUX4 leading to rapid nuclear export, degradation of the fusion, and tumor cell death. Since MAPK
signaling is a ubiquitous pathway expressed in both normal and malignant processes, we wondered
how the CIC-DUX4 fusion could maintain its own expression. Through biochemical and molecular
studies we have identified a key role for negative MAPK-ERK regulation in CIC-DUX4 sarcoma cells.
Whereby, CIC-DUX4 transcriptionally upregulates the ERK specific phosphatase, DUSP6, to limit ERK
activity and thus enable CIC-DUX4 expression. More recently, we made an unexpected finding that
CIC-DUX4 expression could also downregulate RAS activity. Since RAS is a proximal MAPK substrate
not targeted by DUSP6, we hypothesized that CIC-DUX4 was limiting MAPK-RAS-ERK signaling flux
at multiple levels within this canonical signaling cascade. This proposal will define how CIC-DUX4 is
regulating RAS activity, thus further sustaining CIC-DUX4 expression.

## Key facts

- **NIH application ID:** 10818281
- **Project number:** 3R37CA255453-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Ross Okimoto
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $75,236
- **Award type:** 3
- **Project period:** 2021-06-17 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818281

## Citation

> US National Institutes of Health, RePORTER application 10818281, Negative MAPK-RAS-ERK pathway regulation to sustain CIC-DUX4 expression (3R37CA255453-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10818281. Licensed CC0.

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