# Validation of WEE1 kinase as a clinical target in KRAS-mutant pancreatic cancer

> **NIH NIH F30** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $51,036

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related mortality in the United
States. PDAC is the deadliest cancer, with an abysmal 5-year survival rate of 8%. Over 95% of PDAC harbor a
mutationally activated KRAS oncogene, a well-validated driver of PDAC growth. Despite the near-universal
dependence of PDAC on oncogenic KRAS, the development of clinically effective anti-KRAS therapies for PDAC
remains elusive. One promising approach involves inhibition of KRAS effector signaling, particularly inhibitors of
the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cascade. However, I hypothesize that additional
kinases must also contribute to KRAS-driven PDAC growth. To address this possibility, we applied an unbiased
kinome-wide chemical proteomics strategy (MIB-MS) to identify novel KRAS-regulated kinases. Upon acute
KRAS suppression, we identified both upregulated and downregulated kinases. Partnering this dataset with my
analyses of an RNA-Seq dataset profiling the ERK-dependent transcriptome that identified DNA-damage
response (DDR) and cell-cycle regulation gene signatures, I selected the WEE1 DNA damage checkpoint kinase
for further evaluation. My preliminary results determined that mutant KRAS may regulate WEE1 activity through
both gene transcription and increased protein stability. I also found that pharmacologic inhibition of WEE1
suppressed PDAC growth in vitro, but additionally observed ERK activation upon WEE1 inhibition. Speculating
that this ERK activation is a compensatory mechanism that can drive drug resistance, I found that concurrent
ERK and WEE1 inhibition synergistically suppressed PDAC growth in vitro. These results provide the foundation
for my studies and the rationale for my two aims: (1) to delineate the mechanisms by which KRAS regulates
WEE1 expression/abundance and determine how WEE1 loss contributes to KRAS-dependent PDAC growth;
and, (2) to apply advanced preclinical models of PDAC (organoids and syngeneic orthotopic tumors) to assess
the therapeutic impact of the clinical candidate WEE1 inhibitor adavosertib, alone or in combination with the
clinical candidate ERK inhibitor ulixertinitib. The scientific innovation of my studies involves exploiting DNA
checkpoint inhibitors as a therapeutic vulnerability of KRAS-mutant pancreatic cancer, where current standard
of care remains ineffective conventional cytotoxic drugs. My studies will further elucidate basic mechanisms of
KRAS signaling and additionally identify new therapies for clinical evaluation. This research will provide me with
training in cancer cell and molecular biology, preclinical drug assessment, and the implementation of
computational tools for bioinformatics analyses. I will also participate in mentored clinical activities focused on
the care of a diverse set of oncology patients. Overall, the superior research and clinical opportunities at the
University of North Carolina at Chapel Hill, my network of experienced collaborat...

## Key facts

- **NIH application ID:** 10167650
- **Project number:** 5F30CA243253-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** John Nathaniel Diehl
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2019-07-09 → 2023-07-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167650

## Citation

> US National Institutes of Health, RePORTER application 10167650, Validation of WEE1 kinase as a clinical target in KRAS-mutant pancreatic cancer (5F30CA243253-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10167650. Licensed CC0.

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