大细胞神经内分泌癌（LCNEC）是一种高级神经内分泌恶性肿瘤，与小细胞肺癌（SCLC）一样，与缺乏可药物致癌驱动因素和预后不良有关。然而，与 SCLC 相比，几乎没有证据来指导最佳治疗策略，这些策略通常改编自 SCLC 和非小细胞肺癌 (NSCLC) 方法。为了更好地定义 LCNEC 的生物学，我们分析了细胞系和患者基因组数据并对 LCNEC 患者和临床前模型的芯针活检进行了免疫组织化学和单细胞 (sc)RNAseq。在这里，我们证明 YAP1 的存在或不存在可以区分 LCNEC 的两个亚型。 YAP1 高子集是间质性的、发炎的，与 TP53 突变一起，其特征是 CDKN2A/B 和 SMARCA4 中同时发生的改变。在治疗上，YAP1 高子集表现出对 MEK 和 AXL 靶向策略（包括新型临床前 AXL CAR-T 细胞）的脆弱性。同时，YAP1-low 亚群是上皮性和免疫冷的，更常见的特征是 TP53 和 RB1 共突变，与纯 SCLC 中观察到的相似。值得注意的是，YAP1-low 子集的特征还包括 SCLC 亚型定义转录因子的表达，尤其是 ASCL1 和 NEUROD1，而且正如预期的那样，鉴于其与 SCLC 的转录相似性，YAP1-low 亚群表现出令人想起 SCLC 的假定脆弱性，包括 Delta 样配体 3（ DLL3) 和 CD56 靶向，与新型临床前 DLL3 和 CD56 CAR T 细胞一样，以及 DNA 损伤修复 (DDR) 抑制。YAP1 定义了具有独特生物学的不同 LCNEC 子集。这些发现凸显了 YAP1 指导 LCNEC 个性化治疗策略的潜力。

Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with an absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies which are often adapted from SCLC and non-small cell lung cancer (NSCLC) approaches.To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed immunohistochemistry and single-cell (sc)RNAseq of core needle biopsies from LCNEC patients and preclinical models.Here, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and characterized, alongside TP53 mutations, by co-occurring alterations in CDKN2A/B and SMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK and AXL targeting strategies, including a novel preclinical AXL CAR-T cell. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly features TP53 and RB1 co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by expression of SCLC subtype-defining transcription factors - especially ASCL1 and NEUROD1 - and, as expected given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including Delta-like ligand 3 (DLL3) and CD56 targeting, as with novel preclinical DLL3 and CD56 CAR T-cells, and DNA damage repair (DDR) inhibition.YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC.