# Project 1: Glutaminolytic GDH1 activation-dependent immunotherapy resistance in LKB1-mutant lung adenocarcinoma

> **NIH NIH P01** · EMORY UNIVERSITY · 2024 · $399,749

## Abstract

PROJECT SUMMARY
Project 1 of the Emory Lung Cancer P01 application focuses on interrogation of metabolic dysregulation in LKB1-
mutant lung adenocarcinoma (LUAD) to overcome immunotherapy resistance. LKB1, which is inactivated in 25%
of LUAD, plays an important role in regulating cell metabolism. Elevated glutamine metabolism is critical for
cancer progression, but the mechanism by which glutaminolysis is upregulated and contributes to immune
escape is still elusive. We found that glutamate dehydrogenase 1 (GDH1), the crucial enzyme in glutaminolysis
pathway, induces CamKK2, which substitutes for LKB1 to activate AMPK to manage energy homeostasis and
promote metastasis in LKB1-deficient lung cancer. Through kinase inhibitor profiling, we found that focal
adhesion kinase (FAK; focus of Project 3) phosphorylates GDH1 at Y135 and activates GDH1 specifically in
LKB1 mutated LUAD. To investigate the link between GDH1 signaling and antitumor immunity, we performed
immune profiling and demonstrated that GDH1 contributes to promotion of activated regulatory T cells and
attenuation of tumor infiltrated CD8 T cells in vivo. Replenishing energy metabolism in LKB1 mutated lung cancer
with GDH1 loss by reactivating AMPK reduced the enhanced T cell survival in vitro. Through a genomic profiling
of immune checkpoint factors, we also found that GDH1 promotes expression of programmed death-ligand 1
(PD-L1) and poliovirus receptor (PVR), and their potential transcription factor CREB was found to be activated
by GDH1-CamKK2-CamK4 signaling. Furthermore, GDH1 loss resulted in increased protein expression of
stimulator of interferon genes (STING; focus of Project 2). Inhibition of GDH1 using our novel GDH inhibitor R162
attenuated lung cancer progression and rendered LKB1 mutated LUAD cells vulnerable to activated primary
immune cells. Moreover, R162 in combination with PD1 inhibitor further induced cancer cell death compared to
single agent treatment, suggesting GDH1 as a promising target to overcome immunotherapy resistance.
 Thus, our central hypothesis is that FAK activates GDH1 by Y135 phosphorylation specifically in LKB1-
mutant LUAD and provides immunotherapy resistance through metabolic, transcriptional, and protein stability
regulation. Thus, GDH1 represents a promising anti-cancer target in combination with immunotherapy agents
targeting PD-L1/PVR signaling. Three specific aims are proposed: (1) To decipher the mechanism by which
FAK-mediated phosphorylation and activation of GDH1 promotes cancer progression in an LKB1-dependent
manner; (2) To determine how GDH1 confers immunotherapy resistance by providing metabolic, transcriptional,
and protein stability advantages through AMPK, CREB, and STING; and (3) To evaluate the therapeutic efficacy
of targeting GDH1 in combination with -PD-L1/-TIGIT-based immunotherapy. Along with Project 2 (STING)
and Project 3 (FAK), accomplishing the goals of our project is expected to develop novel GDH1-targeted
therapeutic ...

## Key facts

- **NIH application ID:** 10861803
- **Project number:** 5P01CA257906-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Sumin Kang
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $399,749
- **Award type:** 5
- **Project period:** 2022-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861803

## Citation

> US National Institutes of Health, RePORTER application 10861803, Project 1: Glutaminolytic GDH1 activation-dependent immunotherapy resistance in LKB1-mutant lung adenocarcinoma (5P01CA257906-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10861803. Licensed CC0.

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