# Targeting LKB1-null lung adenocarcinoma with innate immune system

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $412,067

## Abstract

Project Summary
The tumor suppressor LKB1 is one of the most frequently mutated genes in lung adenocarcinoma (LUAD). This
tumor subgroup is resistant to immune checkpoint blockade therapy and is not amenable to molecularly targeted
therapies. LUAD with LKB1 mutations is usually smoking-related. Even though females are more susceptible to
smoking-related DNA-adduct formation in the lung, the frequency of LKB1-mutant LUAD is significantly lower in
females than males in multiple large-scale studies. The underlying mechanism is not known primarily because
of the lack of an appropriate model to study this phenomenon. We previously established a genetically
engineered mouse model (GEMM) in FVB/N background, which can form KrasG12D/LKB1null (LUAD) in the lung
with similar features to human LUAD in tumor characteristics and tumor microenvironment. A meta-analysis of
our GEMM model revealed the LUAD formation at 97% in males versus 58% in females. We also established
lung cancer cell lines from our GEMM, and the establishment of lung metastases through tail-vein injection in
syngeneic animals also encountered a strong sex bias in female hosts. Interestingly, this sex bias can also be
observed in immune-compromised mice, such as SCID mice deficient in adaptive immunity. Therefore, we
hypothesize that innate immunity in some female hosts can eliminate LKB1-mutant LUAD. Here, we will (i)
determine why LKB1-mutant LUAD is susceptible to this innate immunity and (ii) which subpopulation of innate
immune cells is responsible for eliminating LKB1-LUAD in some female hosts. The elucidation of this mechanism
should provide novel insights into developing new therapeutic strategies for LKB1-mutant LUAD.

## Key facts

- **NIH application ID:** 10886819
- **Project number:** 5R01CA284648-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Wei Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $412,067
- **Award type:** 5
- **Project period:** 2023-07-12 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886819

## Citation

> US National Institutes of Health, RePORTER application 10886819, Targeting LKB1-null lung adenocarcinoma with innate immune system (5R01CA284648-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10886819. Licensed CC0.

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