# Research Project 2

> **NIH NIH U54** · WASHINGTON UNIVERSITY · 2024 · $199,164

## Abstract

PROJECT 2 SUMMARY
After several decades of intensive efforts from academia and industry, targeting KRAS using KRAS-specific
inhibitors (KRASi) such as sotorasib and adagrasib has finally become a clinical reality. However, clinical
reponses to KRASi vary widely across different cancer types (higher in lung cancer, but much lower in colon and
panceraic cancers) and are typically not durable. Importantly, cancers that eventually became resistant to KRASi
were found to have acquired secondary mutations that restore KRAS signaling. For these patients, there is still
a strong need for therapeutic combinations that can abrogate KRAS signaling pathways such as the RAF-MEK-
ERK (MAPK) or PI3K-AKT cascades. To meet these clinical needs, Project 2 of the WU-PDTC aims at testing
three novel therapeutic combinations to deepen the therapeutic response of KRASi in different KRAS-mutant
cancer PDXs. Because these combinatorial strategies were developed from panceratic cancer models, we will
also preform start-of-the-art proteo-transcriptomic analyses to determine the shared and distinct primary and
secondary resistance mechanisms of pancreatic, lung and colon cancer PDXs to KRAS and MAPK pathwya
inhibtiors. Our project capitalizes on the large repertoire of genetically-defined PDX models from different cancer
types, is based on novel exciting biology, supported by state-of-the-art technqiues including innovative 3D-
heterotypic culture model, spatio-transcriptomics, snRNAseq, multiplex immunohistochemistry and an
outstanding bioinformatic team. We have strong institutional commitment to provide additional fund to ensure
this Project is smoothly executed. Our novel therapeutic concepts are based on therapeutic agents that are
already in clincial trials. If successful, results from our Project can be immediately translated into biomarker-
driven clinical trials under the NCI Experimental Therapeutics Clinical Trials Network, in which WU is an active
participating member.

## Key facts

- **NIH application ID:** 10881789
- **Project number:** 5U54CA224083-06
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Kian H Lim
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $199,164
- **Award type:** 5
- **Project period:** 2017-09-30 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881789

## Citation

> US National Institutes of Health, RePORTER application 10881789, Research Project 2 (5U54CA224083-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10881789. Licensed CC0.

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