# Translation addiction and targeting in colon cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $469,185

## Abstract

Summary
Colorectal cancer (CRC) represents a leading cause of cancer death in the US and worldwide, and its
development is driven by mutational activation of Wnt, RAS/RAF/ERK and PI3K/AKT/mTOR signaling. However,
targeting individual driver in CRC has limited success. Wnt, mTOR and ERK signaling converges to deregulate
eIF4F and lead to translate key oncogenic targets including c-Myc. Interestingly, phosphorylated eIF4E (S209,
or p-eIF4E) is dispensable for development or global translation, but required for transformation and optimal
tumorigenesis in some models. The underlying causes and significance of elevated p-eIF4E in human cancer
and oncogenic translation remains largely unknown. Our novel preliminary data and recent publications supports
a critical role of p-eIF4E in human and mouse colon cancer development, and in regulating colon cancer
proliferation via ATF4-mediated metabolic and stress adaptation. Pharmacological targeting of eIF4E/4F
induces endoplasmic reticulum stress and CRC cell death in culture and in vivo. The central hypothesis of the
project is that phosphorylated eIF4E drives colon cancer initiation and progression through ATF4-dependent
metabolic and stress reprogramming and serves as an actionable and druggable vulnerability. We will test this
hypothesis in three specific Aims. SA1. Define the role of eiF4E phosphorylation in colon cancer development.
SA2. Elucidate the mechanisms of p-eIF4E-dependent oncogenesis in colon cancer. SA3. Target eIF4F/4E in
colon cancer therapy. The proposed work will develop and employ innovative tools, including phosphorylation
defective eIF4E cancer cells and mice, clinical samples, and highly mechanistic and comprehensive approaches
to define the role of p-eIF4E in colon cancer biology and therapy. If successful, our work will provide a better
understanding of oncogenic translation in protective stress and metabolic adaptation, as well as strategies to
target this addiction for therapy. These findings will likely have important implications in treating other cancers
with hyperactive Wnt and RAS/RAF for which no effective therapy currently exists.

## Key facts

- **NIH application ID:** 9847788
- **Project number:** 5R01CA215481-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jian Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,185
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9847788

## Citation

> US National Institutes of Health, RePORTER application 9847788, Translation addiction and targeting in colon cancer (5R01CA215481-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9847788. Licensed CC0.

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