# Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance

> **NIH NIH F30** · DUKE UNIVERSITY · 2020 · $46,300

## Abstract

Abstract
KRAS mutations drive resistance to diverse targeted therapies, most notably to EGFR inhibitors in the setting
of metastatic colorectal cancer (CRC). Curiously however, through a series of genetic screens involving
constitutive activators of oncogenic signaling pathways, we found that ectopic expression of mutant HRAS,
another RAS gene not typically associated with resistance, drove substantially stronger therapeutic resistance
than mutant KRAS. Although HRAS and KRAS share ~85% amino acid sequence identity, the nucleotide
sequence between the two varies enormously, with HRAS being enriched in common codons that yield high
protein expression, while KRAS is enriched in rare codons that yield poor expression. This suggested that rare
codons may limit the ability of KRAS to impart resistance in the clinic. Consistent with this notion, we find that
primary resistance to the EGFR inhibitor cetuximab in CRC is dependent not only upon KRAS mutational
status, but also upon the ability of cancer cells to overcome the translational barrier imposed by codon bias.
Similarly, we show that more potent KRASQ61 mutations drive acquired resistance even in the setting of low
protein expression, perhaps explaining the paradoxical enrichment of these mutations observed in patients
with cetuximab-refractory CRC. Finally, we demonstrate that cancer cells globally upregulate translation in the
setting of KRASG12-driven acquired cetuximab resistance, resulting in hypersensitivity to diverse small
molecule inhibitors of translation. These findings demonstrate that codon bias plays a critical regulatory role in
KRAS-driven therapeutic resistance and provide a mechanistic rationale for targeting protein translation to
overcome resistance.

## Key facts

- **NIH application ID:** 9969056
- **Project number:** 5F30CA220847-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Moiez Ali
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $46,300
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969056

## Citation

> US National Institutes of Health, RePORTER application 9969056, Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance (5F30CA220847-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9969056. Licensed CC0.

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