Pulice John L, Meyerson Matthew
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.
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.
Mol Cell. 2025 Apr 3;85(7):1311-1329.e16. doi: 10.1016/j.molcel.2025.03.001. Epub 2025 Mar 25.
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.
扩增介导的癌基因过表达是癌症中一个关键且普遍存在的驱动事件，但我们对扩增和剂量如何介导癌基因调控的理解有限。在这里，我们发现肺腺癌（LUAD）中最显著的局灶性扩增事件靶向NKX2-1谱系转录因子附近的一个谱系“超级增强子”。NKX2-1超级增强子被局灶性扩增并与NKX2-1共同扩增所靶向，并控制NKX2-1的表达和调控。我们发现NKX2-1直接控制增强子的可及性，以驱动LUAD中的谱系成瘾状态。我们精确绘制了NKX2-1剂量调节对过表达和敲低的影响，并确定了NKX2-1剂量的线性和非线性调节。我们发现NKX2-1在LUAD细胞系中是一种广泛的依赖性，并且NKX2-1赋予对表皮生长因子受体（EGFR）抑制剂的持久性。我们的数据表明剂量在扩增的NKX2-1的致癌调控中起决定性作用，并且扩增的NKX2-1谱系成瘾定义了LUAD肿瘤。
