# NKX2-1 Enhancer Amplification and Lineage Addiction in Lung Adenocarcinoma

> **NIH NIH R35** · DANA-FARBER CANCER INST · 2022 · $94,095

## Abstract

Project Summary
 Lung cancer kills over 135,000 Americans each year, and over a million people annually
world-wide. Thus, there is an urgent need to continue to improve the prevention, diagnosis and
treatment of this deadly disease. Our research focuses on lung adenocarcinoma, the most
common form of lung cancer. Lung adenocarcinoma is, at its root, a disease of the genome. Our
proposed research falls into three broad categories: 1. Single gene alterations: we will analyze
the mechanisms by which both mutations and copy number alterations underlie the
pathogenesis of lung adenocarcinoma. Examples from this proposal include the tumor
suppressor gene CMTR2 and the lineage oncogene NKX2-1, which is the most significantly
amplified gene in lung adenocarcinoma. 2. Immunological target identification: we will use
genomic approaches to characterize immunological features of lung cancer and potential
vulnerabilities. Examples include continued studies of genes involved in RNA sensing &
modification in the interferon pathway that are also cancer dependencies, as well as large-scale
functional genomic screens to identify epitopes that are antigenic targets of T cells in lung
cancer. 3. Genome-wide features. We continue to study aneuploidy and the function of gene
dosage effects on cell growth and proliferation. In addition, we are developing a new approach
for genome-based therapy: nucleic acid cleavage therapies that target the “neo-genome” in lung
cancer DNA. This approach would exploit the novel genomic sequences that result from
chromosomal rearrangements in cancer by using genome engineering tools to specifically target
cancer cells. My goal is that the proposed research will deepen our understanding of human
lung adenocarcinoma and will drive novel, effective treatments for lung cancer patients.
Aim 1: Functional studies of gene level alterations in lung adenocarcinoma
 1a. Functional analysis of the CMTR2 tumor suppressor gene.
 2a. Why is NKX2-1 amplified in lung adenocarcinoma?
Aim 2: Genome-wide approaches to identifying immunological targets in lung adenocarcinoma
 2a. RNA modification pathways: from ADAR to XRN1
 2b. Identifying T cell receptors specific for mutated epitopes in lung cancer
Aim 3: Genome-level alterations in lung adenocarcinoma
 3a. Assessing the role of gene dosage in the impact of chromosome loss
 3b. Targeting the lung cancer neo-genome with nucleic acid therapy

## Key facts

- **NIH application ID:** 10598959
- **Project number:** 3R35CA197568-09S1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Matthew L. Meyerson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $94,095
- **Award type:** 3
- **Project period:** 2015-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598959

## Citation

> US National Institutes of Health, RePORTER application 10598959, NKX2-1 Enhancer Amplification and Lineage Addiction in Lung Adenocarcinoma (3R35CA197568-09S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10598959. Licensed CC0.

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