# Defining the KRAS mutation specific interactions in pancreas cancer

> **NIH NIH P20** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $206,129

## Abstract

Pancreatic cancer is characterized by mutational activation of the “undruggable” KRAS proto-oncogene, 
and approximately 95% of all pancreatic ductal adenocarcinoma (PDAC) patients harbor a KRAS 
mutation. With an abysmal five-year survival rate of 10%, developing effective therapeutic strategies 
remains a high priority. The KRASG12D mutation represents the most common KRAS mutation in PDAC 
followed by KRASG12V and KRASG12R. However, other mutations, such as KRASQ61L, are 
non-existent in PDAC despite being highly oncogenic in model systems. Thus, KRAS mutations are not 
equal, and each mutant may regulate distinct as well as overlapping signaling pathways. We will map the 
protein interactions of specific KRAS mutants utilizing both 2D and 3D cell models. In Aim 1, we will 
employ a new version of Biotin Identification (BioID) proximity ligation assays, termed TurboID, to define 
the mutation-specific protein interactions. My work on KRASG12R provides an excellent example of 
KRAS mutation-specific signaling. We hypothesize that the mutant-specific effector interactions in 
KRAS-initiated PDAC will illuminate which pathways are most susceptible to therapeutic disruption. In Aim 
2, we propose to expand the Cell Models Core of the CDLD to generate mouse- and patient-derived 
pancreatic organoids for use in our studies and others at MUSC. KRAS signaling varies depending on 
whether cells are grown on plastic (2D) vs 3D environments. To address this complexity, we will extend 
our BioID studies into 3D organoids developed from normal mouse pancreas. This approach will allow for 
the use of a “normal” organoid line to define the mutation-specific signaling differences between KRAS 
mutants. The use of normal mouse organoids will allow for an isogenic “normal” environment that is more 
representative of the natural pancreas environment in which KRAS initiates the early stages of pancreatic 
cancer. To validate whether the mutation-selective effector pathways are necessary in an early cancer 
model system, we will establish pre-neoplastic organoids from KrasLSL-G12D/+ and KrasLSL-G12R/+ 
mouse models, where the KRAS mutation is expressed in the native gene locus to validate the potential 
targets. This approach will help define a new class of mutation-specific therapies in pancreatic cancer.

## Key facts

- **NIH application ID:** 10531847
- **Project number:** 5P20GM130457-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Guy Hobbs
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $206,129
- **Award type:** 5
- **Project period:** 2020-04-03 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10531847

## Citation

> US National Institutes of Health, RePORTER application 10531847, Defining the KRAS mutation specific interactions in pancreas cancer (5P20GM130457-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10531847. Licensed CC0.

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