# Understanding the role of RNA-binding protein mutations in cancer

> **NIH NIH P20** · DARTMOUTH COLLEGE · 2024 · $262,332

## Abstract

The identification of therapeutically actionable genetic lesions in malignancies has transformed patient care. 
However, there remain many individuals who either do not possess these targetable alterations or who relapse 
following therapeutic intervention. Therefore, it is imperative to identify novel mechanisms that control the critical 
biological processes that impact clinical outcomes. RNA-binding proteins (RBPs) have emerged as fundamental 
regulators of a plethora of biological processes, and their dysregulation has been established in a variety of solid 
and heme malignancies, making them attractive candidates for study. This application will focus on the role of a 
mutation in an RNA-binding protein, PCBP1, in colorectal cancer initiation and progression. 
Poly-C binding protein 1, PCBP1, is a tumor suppressor that is recurrently mutated in 3% of all colorectal 
cancers. These hotspot missense mutations have been identified as putative cancer drivers in several unbiased 
studies. Critically, a recent study identified PCBP1 mutations as a resistance mechanism to cetuximab therapy 
in colorectal cancer patients. These observations necessitate an in-depth investigation into the pathogenic role 
of PCBP1 mutations. Our preliminary data suggest that the L100Q mutation attenuates the tumor suppressive 
function of PCBP1 and activates oncogenic signaling cascades. 
Our central hypothesis is that the L100Q mutation in the RNA-binding domain of PCBP1 abrogates its tumorsuppressive 
function and promotes malignant phenotypes due to its ability to activate diverse signaling 
cascades. In this proposal we will 1) determine the impact of PCBP1 mutation on the cellular signaling 
landscape, and 2) determine whether the PCBP1 mutants can drive oncogenic transformation and progression. 
Completion of this study will provide insights into the mechanisms by which PCBP1 mutations impact cancer 
signaling pathways, as well as help identify therapeutic vulnerabilities in these pathways. Furthermore, these 
studies will have exciting implications for other structurally-related RBPs implicated in disease. Finally, 
completion of these studies will lend credence to the role of RBPs as therapeutically actionable drivers of 
disease.

## Key facts

- **NIH application ID:** 11055960
- **Project number:** 5P20GM113132-09
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Prerna Malaney
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $262,332
- **Award type:** 5
- **Project period:** 2016-05-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11055960

## Citation

> US National Institutes of Health, RePORTER application 11055960, Understanding the role of RNA-binding protein mutations in cancer (5P20GM113132-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11055960. Licensed CC0.

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