# Identifying the Impact of SETD2 Inactivation in Lung Adenocarcinoma

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $445,882

## Abstract

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.

## Key facts

- **NIH application ID:** 10366169
- **Project number:** 1R01CA262619-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** David Feldser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $445,882
- **Award type:** 1
- **Project period:** 2021-12-10 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366169

## Citation

> US National Institutes of Health, RePORTER application 10366169, Identifying the Impact of SETD2 Inactivation in Lung Adenocarcinoma (1R01CA262619-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10366169. Licensed CC0.

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