# Targeting KRAS and adenosine mediated immunosuppression in pancreatic cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $634,454

## Abstract

PROJECT SUMMARY
Activating KRAS mutations, altered metabolism, and an immunosuppressive tumor microenvironment are all
hallmarks of pancreatic ductal adenocarcinoma (PDAC). The recent groundbreaking discovery of KRASG12C
specific inhibitors has reinvigorated hope for direct targeting of this dominant driver oncogene formerly deemed
“undruggable”. However, it is becoming increasingly clear that the therapeutic potential of mutant KRAS
inhibitors in PDAC and other malignancies will only be realized if they are administered as components of
rationally designed combination therapies. To identify actionable immunomodulatory and metabolic events
triggered by KRASG12C inhibition in PDAC, transcriptomic, proteomic, and metabolomic analyses were
performed in human and murine models. KRASG12C inhibition in pancreatic cancer cells limited the expression
of immunosuppressive chemokines, increased antigen presentation pathways, reduced nutrient (glucose and
glutamine) consumption, and the production of immunosuppressive metabolites (lactate). These studies
indicate that KRASG12C inhibitors exert immune-priming effects in PDAC and support combinations with
immune checkpoint blockade (ICB) agents. However, these immune-priming effects were accompanied by
alterations in nucleotide metabolism and by elevated extracellular adenosine levels. This finding has great
potential significance since adenosine is known to curtail anti-tumor immunity by engaging adenosine A2a/A2b
receptors (A2aR/A2bR) on a broad array of immune cell types. Remaining to be determined, if these
observations are to be exploited for therapeutic purposes in KRASG12C PDAC, are (i) the mechanisms by which
KRASG12C inhibition modulates nucleotide metabolism and adenosine levels in PDAC cells, (ii) the requisite
components of ICB (anti-PD-1 and/or anti-CTLA-4) when co-targeting KRASG12C and A2aR/A2bR in animal
models, and (iii) whether targeting adenosine signaling promotes synergy between KRASG12C inhibition and
ICB in patients with KRASG12C PDAC. Studies proposed in Aim 1 will test the hypothesis that elevations in
adenosine levels induced by KRASG12C inhibition reflect alterations in nucleotide metabolism, leading both to
increased pancreatic tumor cell adenosine efflux and to decreased adenosine uptake. Aim 2 entails
mechanistically-based testing of combinations co-targeting KRASG12C, A2aR/A2bR and conventional immune
checkpoints in new orthotopic, metastatic and genetic murine models of KRASG12C pancreatic cancer. Aim 3
consists of a first-in-human investigator-initiated phase IA/IB clinical trial to test the tolerability and efficacy of
our combinations as second-line therapies in patients with pancreatic cancer. Proposed studies will establish a
new mechanistic framework of interrelationships between KRASG12C inhibition, nucleotide metabolism,
adenosine signaling, and immunosuppression both in mouse models of PDAC and in patients. They will also
provide the foundation for forward and reverse ...

## Key facts

- **NIH application ID:** 10224563
- **Project number:** 1R01CA260678-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Timothy R Donahue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $634,454
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224563

## Citation

> US National Institutes of Health, RePORTER application 10224563, Targeting KRAS and adenosine mediated immunosuppression in pancreatic cancer (1R01CA260678-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10224563. Licensed CC0.

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