# The Role of HER3 and IGF1R, through Non-Classical Ras Signaling, on Malignant Peripheral Nerve Sheath Tumor Progression

> **NIH NIH F30** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $47,680

## Abstract

PROJECT SUMMARY/ABSTRACT 
Currently, no effective treatment for Malignant Peripheral Nerve Sheath Tumors (MPNSTs) exists outside of
radical resection, which has poor long-term survival, putting patients with this aggressive spindle cell neoplasm
in dire need of an effective treatment. Loss of Neurofibromin 1 (NF1) and subsequent Ras activation are
hallmarks of this disease. Proposed therapies targeting Ras and its downstream effectors have failed, so we
are exploring targeting upstream activators of Ras, specifically Receptor Tyrosine Kinases (RTKs), which are
activated in a positive feedback loop as a result of NF1 loss. Using pharmacologic and genetic screens, we
assessed the contribution of all 58 RTKs in MPNST proliferation and survival, identifying the HER receptor
HER3 and Insulin-like Growth Factor 1 Receptor (IGF1R) as critical for MPNST progression. Subsequent
validation experiments with the broad spectrum HER inhibitor canertinib and an IGF1R inhibitor,
picropodophylin (PPP), showed a decrease in proliferation of MPNST cells, with a statistically significant
decrease in cell viability with combination treatment. Levels of activated Ras and phosphorylated Erk1/2 were
also reduced following combinatorial treatment. While our preliminary data show a decrease in proliferation of
MPNST cells and reduced expression of IGF1R initially after HER3 ablation, we observe that in late passage
cells, there is a subsequent increase in IGF1R expression and a rescue in proliferation, suggesting
compensation and cooperation between the two RTKs. Our preliminary studies also link HER3 to R-Ras family
member proteins, specifically linking loss of HER3 with reduced activation of activated R-Ras and R-Ras2. We
have explored the role of R-Ras in MPNST migration and invasion, finding a decrease in migration and loss of
invasive phenotype after loss of R-Ras family members (via dominant negative vector expression). We
propose to rigorously test the hypothesis that HER3 and IGF1R cooperatively promote MPNST
progression and modulate migration and invasion through isoform-specific activation of R-Ras
proteins and downstream signal transduction pathways of Raf/MEK/ERK and PI3K/AKT; this will be
accomplished through 2 aims: first, examining the cooperation of HER3 and IGF1R as activators of Ras
isoforms to drive proliferation, migration and invasion, and secondly by testing combinatorial therapy with
HER3 and IGF1R inhibitors as a novel approach to effectively inhibit tumor growth when compared to
monotherapy with either agent alone. We hope to elucidate the mechanism of RTKs and Ras isoforms on
MPNST progression, coupled with identifying a novel combinatorial therapeutic strategy for those suffering
from this and other NF1 driven diseases.

## Key facts

- **NIH application ID:** 9908563
- **Project number:** 1F30CA247139-01
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Shannon Weber Doutt
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,680
- **Award type:** 1
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908563

## Citation

> US National Institutes of Health, RePORTER application 9908563, The Role of HER3 and IGF1R, through Non-Classical Ras Signaling, on Malignant Peripheral Nerve Sheath Tumor Progression (1F30CA247139-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9908563. Licensed CC0.

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