2. Academic Validation
  3. Amplified dosage of the NKX2-1 lineage transcription factor controls its oncogenic role in lung adenocarcinoma

Amplified dosage of the NKX2-1 lineage transcription factor controls its oncogenic role in lung adenocarcinoma

  • Mol Cell. 2025 Apr 3;85(7):1311-1329.e16. doi: 10.1016/j.molcel.2025.03.001.
John L Pulice 1,  Matthew Meyerson 2
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Biological and Biomedical Sciences Program, Harvard University, Cambridge, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA. Electronic address: matthew_meyerson@dfci.harvard.edu.
PMID: 40139189 DOI: 10.1016/j.molcel.2025.03.001
Abstract

Amplification-mediated oncogene overexpression is a critical and widespread driver event in Cancer, yet our understanding of how amplification and dosage mediate oncogene regulation is limited. Here, we find that the most significant focal amplification event in lung adenocarcinoma (LUAD) targets a lineage "super-enhancer" near the NKX2-1 lineage transcription factor. The NKX2-1 super-enhancer is targeted by focal and co-amplification with NKX2-1 and controls NKX2-1 expression and regulation. We find that NKX2-1 directly controls enhancer accessibility to drive a lineage-addicted state in LUAD. We precisely map the effects of NKX2-1 dosage modulation upon both overexpression and knockdown and identify both linear and non-linear regulation by NKX2-1 dosage. We find that NKX2-1 is a widespread dependency in LUAD cell lines and that NKX2-1 confers persistence to EGFR inhibitors. Our data suggest a defining role for dosage in the oncogenic regulation of amplified NKX2-1 and that amplified NKX2-1 lineage addiction defines LUAD tumors.

Keywords

EGFR; NKX2-1; amplification; copy number; dosage; enhancer; gene regulation; lung adenocarcinoma; oncogene; transcription factor.

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