# Deciphering LKB1-associated immunotherapy resistance in lung adenocarcinoma (LUAD)

> **NIH NIH P01** · EMORY UNIVERSITY · 2024 · $2,055,632

## Abstract

SUMMARY
Lung cancer is the leading cancer killer in the United States. Our team proposes to develop novel personalized
therapeutic strategies by exploiting vulnerabilities and opportunities created by alterations in tumor suppressors
in lung cancer. Specifically, we focus on the tumor suppressor LKB1, which is one of the most commonly mutated
genes in lung adenocarcinoma (LUAD); LKB1 mutations are detected in 15-25% of LUAD, representing a major
subpopulation of lung cancer patients. Despite the frequency, upward trajectory of incidence, and aggressive
nature of disease, patients with LKB1-mutant LUAD not only have no targeted therapeutics available, but also
show poor response to immune checkpoint inhibitors, demanding urgent development of effective therapeutic
options. To address this critical gap, our revised application will capitalize on our integrated understanding of
LKB1-loss–evoked tumor growth regulatory mechanisms and suppression of anticancer immunity to develop
innovative clinical approaches for the treatment of patients with LKB1-mutant LUAD. New preliminary data from
our team showed that 1) LKB1 loss allows metabolic dysregulation, such as glutamate dehydrogenase (GDH)
activation by FAK, leading to increased regulatory T cells and immune suppression; 2) LKB1-loss-triggered
inhibition of STING, a key innate immunity regulator, can be reversed by an IAP inhibitor, leading to reactivated
immune response and its potent in vivo immune-dependent anticancer effect; and 3) FAK is activated in LKB1-
deficient cancer cells and supports cell invasion and inhibits immune infiltration. These results lead to our central
hypothesis that mutated LKB1 may exert its immune suppression function through a dysregulated anti-cancer
immunity cycle mediated by key metabolic, innate immunity, and stromal regulatory factors. Targeting these
factors may lead to novel approaches to re-activate anticancer immunity for effective therapeutic development
in LUAD. We will address this hypothesis through three highly integrated Projects. Project 1 will examine the role
of the FAK-GDH1 axis in immunotherapy resistance and tumor progression of LKB1-mutant LUAD. Project 2
will exploit our recently discovered LKB1-regulated IAP-JAK-STING signaling in LUAD to reverse immune
suppression with an IAP inhibitor to enhance immunotherapy effect. Project 3 will focus on targeting FAK-
mediated primary tumor progression in LKB1-mutant LUAD by performing a clinical trial with the combination of
a FAK inhibitor and an immune checkpoint inhibitor coupled with mechanistic studies. The projects are supported
by three cores, whose functions are administrative (Core 1), molecular pathology and immunology (Core 2), and
bioinformatics and biostatistics (Core 3). This highly integrated effort builds on new discoveries from our
established lung cancer team with more than 100 co-publications and with strong institutional support. We expect
to advance lung cancer treatment strategies by ne...

## Key facts

- **NIH application ID:** 10861801
- **Project number:** 5P01CA257906-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Haian Fu
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,055,632
- **Award type:** 5
- **Project period:** 2022-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861801

## Citation

> US National Institutes of Health, RePORTER application 10861801, Deciphering LKB1-associated immunotherapy resistance in lung adenocarcinoma (LUAD) (5P01CA257906-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10861801. Licensed CC0.

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