# Project 2: Reversing STING-mediated immunosuppression in LKB1-mutant lung adenocarcinoma

> **NIH NIH P01** · EMORY UNIVERSITY · 2024 · $415,518

## Abstract

SUMMARY
Project 2 of the Emory Lung Cancer P01 application focuses on the dissection of suppressed anticancer
immunity mechanisms involving STING in lung adenocarcinoma (LUAD) with LKB1 mutations for translational
gains. Lung cancer is the leading cause of cancer death in the US with limited therapeutic options. While
molecularly targeted therapies are effective in patients with defined mutations such as those in EGFR and ALK,
immune checkpoint inhibitors (ICI) have brought hope for additional patients and have revolutionized cancer
therapy to stimulate the host immune system to destroy tumors. Unfortunately, the majority of lung cancer
patients show poor response to such ICIs. In particular, LUAD patients with LKB1 mutations have no targeted
therapies and are unresponsive to ICIs. Thus it is urgent to understand the tumor-immune interactions in such
LKB1-mutant LUAD and develop new therapeutic approaches to overcome immunotherapy resistance. It
appears that the immune suppressed state of LKB1-mutant LUAD is associated with the silenced STimulator of
INterferon Gene (STING), a cytosolic DNA sensor that regulates innate immunity. Thus, strategies to reverse
STING expression may re-establish the tumor-immune microenvironment and re-sensitize tumors for effective
treatment with STING agonists or ICIs. We discovered that birinapant, a small molecule antagonist of Inhibitor
of Apoptosis Protein (IAP), can restore STING expression, reactivate STING signaling, and enhance immune
effector cell killing of LKB1-mut LUAD cells. In further support of this revised application, our new data showed
that birinapant exhibited potent in vivo immune-dependent anti-tumor activity selectively in immune competent
LKB1-mutant mouse model. These results led to our central hypothesis that LKB1 loss is associated with STING
downregulation through aberrant IAP functions, and pharmacological targeting using IAP inhibitors may restore
STING expression and re-establish immune response pathways in LKB1-mut LUAD for enhanced therapeutic
efficacy. To test this hypothesis, we propose to use a combination of cell, mouse, and patient tumor tissues from
Core 2 and Project 3 clinical trials 1) to examine the molecular mechanisms by which IAP inhibitors induce
STING expression in LKB1-mut LUAD cells; 2) to determine the therapeutic effect of IAP inhibitors and STING
agonists in LKB1-mut tumors; and 3) to evaluate the therapeutic effect of IAP inhibitors in combination with a
PD-1 blockade agent in LKB1-mut tumors. We will examine the impact of the IAP-STING axis in the context of
GDH1 (Project 1) and FAK hyperactivation (Project 3) to improve mechanistic understanding of LKB1 immune
response signaling. Accomplishing the goals of the proposal, we aim to deliver preclinical evidence for using IAP
inhibitors, such as birinapant, alone or in combination with STING agonists or ICI to treat lung cancer patients
with LKB1 alterations.

## Key facts

- **NIH application ID:** 10861806
- **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:** $415,518
- **Award type:** 5
- **Project period:** 2022-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861806

## Citation

> US National Institutes of Health, RePORTER application 10861806, Project 2: Reversing STING-mediated immunosuppression in LKB1-mutant lung adenocarcinoma (5P01CA257906-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10861806. Licensed CC0.

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