# Lung Adenocarcinoma: From Genome Alterations to Therapeutic Discovery

> **NIH NIH R35** · DANA-FARBER CANCER INST · 2024 · $992,188

## Abstract

Project Summary
The introduction of new targeted therapies and immunotherapies has led to significant decreases in lung cancer
mortality in the United States in recent years. However, lung cancer continues to kill over 135,000 Americans
each year, and over a million people annually world-wide. Thus, there remains 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. The focus of my laboratory is to understand somatic
genome alterations in human lung cancer, to use this understanding to elucidate lung cancer pathogenesis, and
in turn to improve diagnosis and treatment. We have been honored to participate in many clinically impactful
genomic discoveries, including the discoveries of BRAF and EGFR mutations that guide targeted therapy use.
 In recent work, we continue to advance knowledge of lung cancer genomes and their function. We
described novel oncogenic mutations in lung cancer, the duplication of super-enhancer elements near
known oncogenes. We analyzed the cancer-causing activity of lung adenocarcinoma mutated genes such
as SOS1 and MGA; we initiated genomic approaches to immunological targets such as the ADAR RNA
deaminase gene; and we generated a genomically engineered model of aneuploidy for lung cancer.
 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 described in 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 shown here 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 knowledge gained from the proposed research will deepen our understanding of
human lung adenocarcinoma and will drive novel and effective treatments for lung cancer patients.

## Key facts

- **NIH application ID:** 10889141
- **Project number:** 5R35CA197568-11
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Matthew L. Meyerson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $992,188
- **Award type:** 5
- **Project period:** 2015-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889141

## Citation

> US National Institutes of Health, RePORTER application 10889141, Lung Adenocarcinoma: From Genome Alterations to Therapeutic Discovery (5R35CA197568-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10889141. Licensed CC0.

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