# Investigating the molecular mechanisms of growth in GNAS mutant pancreatic cancer.

> **NIH NIH R37** · UNIVERSITY OF CINCINNATI · 2022 · $370,575

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States with
five-year survival after detection is less than 10%. The subset of PDA arises from Intraductal papillary mucinous
neoplasm (IPMNs) precursor lesions are distinguished by recurrent activating mutations in GNAS, that encodes
G-protein Gαs, and induces cyclic-AMP (cAMP) signaling. GNAS is mutationally activated and amplified
pancreatic and many other human tumors, yet its oncogenic functions remain unclear. Therefore, understanding
the function of mutant GNAS will provide disease mechanisms and give opportunities to treat PDA even in their
early stages. To understand the function of oncogenic GNAS we established a doxycycline-tunable mouse model
and showed that mutant GNAS cooperates with oncogenic KRAS to initiate IPMNs that progress to invasive
PDA upon p53 loss. GNAS remains critical for the maintenance of established tumors, via a protein kinase A
(PKA)-dependent network and resulting inhibition of salt-inducible kinases (SIK1-3). We demonstrated that this
network prominently reprograms metabolic pathways which are potential alternative sources of TCA cycle
metabolites, respiratory substrates (NADH) and fatty acid intermediates that can support the growth of GNAS
mutant tumors. Importantly, GNAS-mutant cancer cells are specifically sensitive to the inhibition of these
pathways compared to GNAS-wt tumors. These results establish mutant GNAS as a novel tumor maintenance
driver, uncover the underlying PKA-dependent program, establish SIKs as major tumor suppressors, and
demonstrate unanticipated metabolic heterogeneity fueling subsets of pancreatic cancer. Based on our
published and unpublished supporting data, the overarching goal of this proposal is to understand the roles of
critical downstream targets of GNAS-PKA signaling that control the expression of proliferation and metabolic
genes. Our research will also illuminate how mutant GNAS regulated expression of a keto dehydrogenase
generate biosynthetic and bioenergetic intermediates to support tumor growth. Finally, our study will interrogate
the regulation of respiratory activity and its requirement in GNAS mutant pancreatic cancer. This study will
leverage advanced methods and unique tools, including global transcriptomic analysis and isotopomer-based
metabolic profiling in genetically defined mouse and human organoid systems, preclinical pancreatic cancer
animal models, relevant patient-derived xenograft systems and primary samples. Our research will provide
understanding of the unique biology of mutant GNAS and points out targetable vulnerabilities in genetic subsets
of pancreatic tumors.

## Key facts

- **NIH application ID:** 10500091
- **Project number:** 1R37CA272854-01
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Krushna Chandra Patra
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $370,575
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10500091

## Citation

> US National Institutes of Health, RePORTER application 10500091, Investigating the molecular mechanisms of growth in GNAS mutant pancreatic cancer. (1R37CA272854-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10500091. Licensed CC0.

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