Wednesday, December 17, 2025 12/17/2025

Identifying the Impact of SETD2 Inactivation in Lung Adenocarcinoma

Award Number: R01CA262619
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/10/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Identifying the Impact of SETD2 Inactivation in Lung Adenocarcinoma - PROJECT SUMMARY SETD2 is mutationally inactivated in many cancer types including lung adenocarcinoma. In published work, we demonstrated that Setd2 inactivation has potent tumor promoting effects in an autochthonous mouse model of KRASG12D-driven lung adenocarcinoma. SETD2 uniquely catalyzes histone H3 lysine 36 trimethylation (H3K36me3), which marks actively transcribed gene bodies, facilitating chromatin resetting after gene transcription. In the current project, we aim to understand the provocative observation that SETD2 inactivation potently drives tumor cell proliferation due to a defect in one-carbon metabolism and activation of mTORC1 signaling. We demonstrate that SETD2 loss is associated with an enrichment in the abundance of S- adenosyl methionine (SAM) and multiple other metabolites that are part of SAM-adjacent metabolic pathways. We will test the hypothesis that the disuse of SAM that results from the lost activity of the SETD2 methyltransferase leads to SAM accumulation, enhanced one-carbon metabolism, and activation of mTORC1 signaling, all supporting cell growth and proliferation. Consistent with this hypothesis, we demonstrate that limiting dietary intake of methionine reduces KRAS-driven lung adenocarcinoma growth and reverses the effects of SETD2 inactivation. Thus, we will assess the efficacy of clinical and pre-clinical drugs that target the methionine cycle for potential synthetic lethal interactions with SETD2 deficiency. Finally, downstream of activated mTORC1 signaling we observe prominent transcriptional programs of hypoxia inducible factors (HIFs) and peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1 α (PGC1α). Consistently, we observe multiple pathophysiological changes that are associated with increased activation of HIF and PGC1α transcription, such as alterations in mitochondrial biogenesis and the co-enhancement of oxidative phosphorylation and glycolytic pathways. Thus, we will test the requirement of these master transcription factors for effectuating phenotypes downstream of SETD2 inactivation.


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: 2026 ( Subtotal = $393,024 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	5	12/10/2025	NON-COMPETING CONTINUATION	$393,024
														Subtotal = $393,024

Issue Date FY: 2025 ( Subtotal = $434,444 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	4	12/4/2024	NON-COMPETING CONTINUATION	$390,999
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	4	6/23/2025	NON-COMPETING CONTINUATION	$43,445
														Subtotal = $434,444

Issue Date FY: 2024 ( Subtotal = $410,628 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	3	4/15/2024	NON-COMPETING CONTINUATION	$21,613
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	3	11/17/2023	NON-COMPETING CONTINUATION	$389,015
														Subtotal = $410,628

Issue Date FY: 2023 ( Subtotal = $439,136 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	2	3/15/2023	NON-COMPETING CONTINUATION	$35,847
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	2	11/24/2022	NON-COMPETING CONTINUATION	$403,289
														Subtotal = $439,136

Issue Date FY: 2022 ( Subtotal = $445,882 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	1	12/10/2021	NEW	$445,882
														Subtotal = $445,882

Grand Total All Awards = $2,123,114

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Identifying the Impact of SETD2 Inactivation in Lung Adenocarcinoma

Award Number: R01CA262619

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/10/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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