# Elucidate the mechanism of autophagy in supporting Lkb1-deficient lung tumorigenesis and metastasis

> **NIH NIH R01** · RBHS -CANCER INSTITUTE OF NEW JERSEY · 2022 · $362,982

## Abstract

Abstract Lung cancer is the leading cause of cancer mortality, with non-small cell lung cancer (NSCLC)
accounting for more than 85% of these cases. KRAS, the most common oncogenic driver in NSCLC, confers a
poor prognosis with limited treatment options. LKB1 is the third most frequently mutated gene in NSCLC. The
mutations in both KRAS and LKB1 account for about 30% of NSCLC, with increased aggressiveness, a high
frequency of metastases and resistance to therapeutics. Autophagy degrades proteins and organelles and
recycles them to provide metabolic substrates, a function that is critical when extracellular nutrients are limited.
Although the role of autophagy in cancer has been intensively studied, the precise role of autophagy in cancer,
especially in vivo, remains elusive and controversial. Moreover, targeting autophagy to treat cancer generally
has not contributed significantly to the advancement of clinical trials. Therefore, identifying genetic vulnerability
that renders strong sensitivity to autophagy inhibition is urgently needed to improve autophagy targeted-
therapies. LKB1 regulates energy homeostasis by activating AMP-activated protein kinase (AMPK), which
inhibits catabolic processes and upregulates anabolic processes, in response to energy crisis. Based on earlier
studies, we began to test the hypothesis that loss of LKB1 promotes cancer cell proliferation but also restricts
adaptation to metabolic stress, a property that may be further compromised by loss of autophagy. Using
genetically engineered mouse models (GEMMs) of NSCLC, we found that autophagy inhibition was synthetically
lethal in KrasG12D/+;Lkb1-/- (KL) mediated tumorigenesis; in contrast to KL lung tumors with intact autophagy, loss
of an essential autophagy gene, Atg7, dramatically impaired both tumor initiation and tumor growth. This is in
sharp contrast to wild-type LKB1 (KrasG12D/+;p53-/-) tumors that are much less sensitive to essential autophagy
gene ablation. Our in vitro study further revealed that autophagy modulates lipid metabolism essential for KL
cancer cells to survive nutrient starvation. These observations indicate that LKB1 mutations predispose KRAS-
driven NSCLC to autophagy inhibition and that LKB1 mutations could be explored as a predictive biomarker for
precision lung cancer therapy. Based on our recent findings, we form our central hypothesis: autophagy
compensates for LKB1 loss by maintaining the metabolism of Lkb1-deficient Kras-driven lung tumors and
promoting their metastasis. We will test this with following specific aims: Aim 1. Elucidate the mechanism by
which autophagy regulates lipid metabolism and KL tumorigenesis in vivo. Aim 2. Determine how autophagy
promotes KL tumor metastasis. Aim 3. Identify metabolic bypasses that potentially create resistance to
autophagy inhibition in KL NSCLC. Successful completion of this proposal will: (1) yield new insights into the role
of autophagy in modulating cellular metabolism in support of KL lung tumo...

## Key facts

- **NIH application ID:** 10329966
- **Project number:** 5R01CA237347-03
- **Recipient organization:** RBHS -CANCER INSTITUTE OF NEW JERSEY
- **Principal Investigator:** Yanxiang Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $362,982
- **Award type:** 5
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329966

## Citation

> US National Institutes of Health, RePORTER application 10329966, Elucidate the mechanism of autophagy in supporting Lkb1-deficient lung tumorigenesis and metastasis (5R01CA237347-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10329966. Licensed CC0.

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