# Characterizing the role of FOXA1 and FOXA2 in NKX2-1 positive lung adenocarcinoma

> **NIH NIH F31** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $33,476

## Abstract

PROJECT ABSTRACT
Lung cancer is the leading cause of cancer death worldwide. Although lung cancer rates have
been steadily decreasing since the early 1990’s, it is still the deadliest cancer in the country, killing
twice as many people in 2017 as the next four types of cancer combined. Lung adenocarcinoma
is the most frequently diagnosed subtype of lung cancer, and approximately 25% of all LUAD
cases are driven by Kras mutations. In patients, KRAS driven lung adenocarcinomas are
significantly heterogeneous in cell identity and differentiation state; these characteristics correlate
directly with patient prognosis and response to available therapies. Currently, the field lacks a
comprehensive understanding of what governs LUAD cell identity and how these
regulatory networks impact malignant potential. Identifying the master transcriptional
regulators and the impact of their inactivation will provide novel insight into the mechanisms of
cancer progression and lay the groundwork for the development of therapeutic strategies specific
to tumor differentiation state. NKX2-1 is a master regulator of pulmonary identity in both healthy
lung and neoplastic tissue. FOXA1 and FOXA2 (FOXA1/2) bind adjacent to NKX2-1 throughout
the genome in both human and murine LUAD. NKX2-1 acts to retain a pulmonary differentiation
state in LUAD in part by controlling FOXA1/2 binding at lineage-specific gene regulatory elements.
FOXA1/2 directly interact with the DNA binding domain of NKX2-1; this interaction enhances
NKX2-1 activity at promoters that also contain FOXA binding sites. It is also known that NKX2-1
coordinates with many other transcription factors and cofactors to facilitate the activation of lung-
specific target genes. The objective of this grant is to identify cancer-relevant functions of FOXA1
and FOXA2 in lung adenocarcinomas that exhibit pulmonary differentiation by retaining NKX2-1
expression. We hypothesize that NKX2-1, FOXA1 and FOXA2 coordinately regulate growth,
survival, and differentiation in LUAD. To test this hypothesis, we will examine how FOXA1 and
FOXA2 govern LUAD cell identity and malignancy in established tumors, determine the impact of
Foxa1/2 deletion on NKX2-1 transcriptional activity, and define the mechanisms by which tumors
can escape the antiproliferative impact of Foxa1/2 deletion.

## Key facts

- **NIH application ID:** 9991592
- **Project number:** 1F31CA243427-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Grace Orstad
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,476
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991592

## Citation

> US National Institutes of Health, RePORTER application 9991592, Characterizing the role of FOXA1 and FOXA2 in NKX2-1 positive lung adenocarcinoma (1F31CA243427-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9991592. Licensed CC0.

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