# Targeting PYK2 for the treatment of PDAC

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $357,994

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all major cancers
and is the third and soon to be the second leading cause of cancer-related deaths in the United
States. The average life expectancy after diagnosis with metastatic disease is just three to six
months. There obviously is an urgent and unmet need for novel effective therapeutic
approaches, but identifying therapeutic targets that will increase survival rates of PDAC patients
remains one of the greatest challenges in current cancer research. Since nearly 100% of
pancreatic ductal adenocarcinoma (PDAC) carried mutational activation of KRAS, KRAS is
theoretically ideal candidate for PDAC therapeutic intervention. But targeting KRAS directly has
been unsuccessful. As a result, there is significant interest in identifying novel downstream
effectors of oncogenic KRAS signaling that could be amenable to pharmacologic intervention.
PYK2 (proline-rich tyrosine kinase 2) is a non-receptor cytoplasmic tyrosine kinase, which is
expressed at a very low level in normal pancreas. We found that PYK2 was drastically induced
in mouse PanIN (pancreatic intraepithelial neoplasia, non-invasive precursor lesions of PDAC)
and human PDAC tissues and that PYK2 elevation required KARS and occurred at the
transcriptional level. Functionally, our results showed that whole-body deletion of PYK2, even
heterozygous deletion, remarkably suppressed PanIN formation in the Pdx1-Cre KRASG12D
mouse model. Further, we found that shRNA knockdown of PYK2 abrogated tumor growth in a
PDAC cell line xenograft model, suggesting that PYK2 is required for PDAC maintenance.
Mechanistically, our data revealed that PYK2 regulates two cancer-related pathways: the Wnt/-
catenin pathway and the NF-B pathway, both pathways are known important for PDAC
genesis and progression. Overall, our preliminary results strongly suggested that PYK2 is a new
functionally relevant and druggable target for PDAC. Our central hypothesis of this study is that
PYK2 is a novel downstream effector of mutant KRAS signaling essential for PDAC
carcinogenesis and maintenance and a new actionable target for treating PDAC. We will test our
hypothesis through the following Specific Aims. Aim 1 will validate the role of PYK2 in mutant
KRAS-driven PDAC carcinogenesis. Aim 2 will unravel how PYK2 is hard-wired among mutant
KRAS-activated signaling networks. Aim 3 will validate PYK2 inhibition as an actionable and
effective approach to treating PDAC in preclinical models of PDAC. Successful completion of the
aims could prove that PYK2-targeted therapy represents an exciting and potentially promising
new approach to treating pancreatic cancer.

## Key facts

- **NIH application ID:** 10072043
- **Project number:** 5R01CA236965-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** JING HU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,994
- **Award type:** 5
- **Project period:** 2019-12-16 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072043

## Citation

> US National Institutes of Health, RePORTER application 10072043, Targeting PYK2 for the treatment of PDAC (5R01CA236965-02). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10072043. Licensed CC0.

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