NKX2-1 Enhancer Amplification and Lineage Addiction in Lung Adenocarcinoma

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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