Monday, June 30, 2025 6/30/2025

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

Award Number: R01CA237347
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Elucidate the mechanism of autophagy in supporting Lkb1-deficient lung tumorigenesis and metastasis - 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 tumorigenesis and metastasis; (2) validate the novel concept that autophagy inhibition is a selective and powerful therapeutic strategy against primary and metastatic KL NSCLC; and (3) reveal metabolic bypass as a potential mechanism of therapy resistance.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $281,978 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	002	6	6/2/2025	NON-COMPETING CONTINUATION	$28,197
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	001	6	2/13/2025	NON-COMPETING CONTINUATION	$0
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	000	6	1/8/2025	NON-COMPETING CONTINUATION	$253,781
														Subtotal = $281,978

Issue Date FY: 2024 ( Subtotal = $51,393 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	002	5	2/8/2024	NON-COMPETING CONTINUATION	$33,847
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	003	5	4/17/2024	NON-COMPETING CONTINUATION	$17,546
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	001	4	12/13/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$252,660
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Biology Research	000	3	12/13/2023	NON-COMPETING CONTINUATION	-$252,660
														Subtotal = $51,393

Issue Date FY: 2023 ( Subtotal = $352,838 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	001	4	2/1/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$352,838
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	3	2/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $352,838

Issue Date FY: 2022 ( Subtotal = $362,982 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	001	3	4/27/2022	NON-COMPETING CONTINUATION	$29,041
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	3	1/4/2022	NON-COMPETING CONTINUATION	$326,682
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	002	3	8/23/2022	NON-COMPETING CONTINUATION	$7,259
														Subtotal = $362,982

Issue Date FY: 2021 ( Subtotal = $361,630 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	001	2	1/15/2021	NON-COMPETING CONTINUATION	$361,630
2021	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	1	10/30/2020	NEW	$0
														Subtotal = $361,630

Issue Date FY: 2020 ( Subtotal = $376,352 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	001	1	1/23/2020	NEW	$9,069
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	1	11/29/2019	NEW	$367,283
														Subtotal = $376,352

Grand Total All Awards = $1,787,173

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

Award Number: R01CA237347

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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