# Identifying Novel Intensity-Specific Regulators of RAS Signaling

> **NIH NIH K22** · DUKE UNIVERSITY · 2024 · $128,993

## Abstract

Abstract
The mammalian family of RAS small GTPases, composed of HRAS, NRAS, and KRAS, is mutated to remain in
an active, oncogenic state in one fifth of all human cancers. Typically, these mutations occur early, initiating
tumorigenesis. Of the three family members, KRAS is mutated most often, suggesting that some feature of this
gene renders it more likely to initiate tumorigenesis. To this end, our group linked the high frequency with which
KRAS is mutated to a bias of rare codons and resulting poor translation of the encoded mRNA. Mechanistically,
the lower levels of KRAS protein and KRAS/MAPK signaling intensity circumvent the growth arrest response of
senescence, thereby allowing the induction of tumor initiation. Conversely, poor translation of KRAS mRNA is
overcome in later disease stages, promoting tumor progression. Thus, different levels of KRAS/MAPK signaling
intensity dictate distinct phenotypic outputs during cancer initiation and progression. Therefore, there must be
factors that differentially control Ras signaling intensity, and these factors should be critical during either tumor
initiation or tumor progression. Such regulators are of great clinical relevance and could open up the door to a
whole new class of regulators of Ras signaling for therapeutic intervention. My long-term goal is to identify
and therapeutically target “RAS intensity-specific regulators”. To identify these regulators, our group took
advantage of the incredible sensitivity of the Drosophila rough eye phenotype to differential levels of Ras
signaling. We employed the novel approach of altering codon usage in the Ras gene of Drosophila to compare
high and low Ras signaling. We then exploited these two genetic backgrounds to execute the first-ever in vivo
intensity-specific regulator screen and identified fifteen deficiencies. One deficiency was mapped to the
Ribosomal protein S21 (Rps21) gene, which acts as a suppressor of Ras signaling. I therefore plan to investigate
the underlying mechanism by which Rps21 suppresses Ras signaling (Aim 1). In addition, I aim to identify other
novel intensity-specific regulators of Ras signaling in the remaining deficiencies and elucidate their roles in Ras
tumorigenesis in the mammalian setting (Aim 2). Completion of these aims will establish new connections
between translational control and Ras signaling, reveal new genetic vulnerabilities in RAS-driven cancer, and
finally could unearth a pipeline of potential therapeutic targets to explore for cancer therapies.

## Key facts

- **NIH application ID:** 10853029
- **Project number:** 5K22CA266753-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Zahra Kabiri
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $128,993
- **Award type:** 5
- **Project period:** 2022-07-19 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853029

## Citation

> US National Institutes of Health, RePORTER application 10853029, Identifying Novel Intensity-Specific Regulators of RAS Signaling (5K22CA266753-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10853029. Licensed CC0.

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