Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2024 Oct 15;30(20):4743-4754. doi: 10.1158/1078-0432.CCR-24-0361.
Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with the 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 approaches.
To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed IHC and single-cell RNA sequencing of core needle biopsies from patients with LCNEC and preclinical models.
In this study, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and is 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 chimeric antigen receptor-expressing 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 the 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 and CD56 targeting, as is with novel preclinical delta-like ligand 3 and CD56 chimeric antigen receptor-expressing T cells, and DNA damage repair inhibition.
YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC.
大细胞神经内分泌癌（LCNEC）是一种高级别神经内分泌恶性肿瘤，与小细胞肺癌（SCLC）一样，缺乏可靶向的致癌驱动因素，预后不良。然而，与 SCLC 不同的是，几乎没有证据可以指导最佳的治疗策略，这些策略通常是从 SCLC 和非小细胞肺癌的方法中改编而来的。
为了更好地定义 LCNEC 的生物学特性，我们分析了细胞系和患者的基因组数据，并对 LCNEC 患者和临床前模型的核心针活检进行了免疫组化和单细胞 RNA 测序。
在这项研究中，我们证明了 YAP1 的存在或缺失将 LCNEC 分为两个亚组。YAP1 高亚组是间充质和炎症的，并且伴随着 TP53 突变，还存在 CDKN2A/B 和 SMARCA4 的共发生改变。在治疗上，YAP1 高亚组对 MEK 和 AXL 靶向治疗策略表现出脆弱性，包括一种新型的临床前 AXL 嵌合抗原受体表达 T 细胞。同时，YAP1 低亚组是上皮和免疫冷的，更常见的特征是 TP53 和 RB1 共突变，类似于纯 SCLC 中观察到的突变。值得注意的是，YAP1 低亚组还表现出 SCLC 亚型定义转录因子的表达，特别是 ASCL1 和 NEUROD1，并且由于其与 SCLC 的转录相似性，预计会表现出类似于 SCLC 的潜在脆弱性，包括针对 Delta 样配体 3 和 CD56 的靶向治疗，以及新型临床前 Delta 样配体 3 和 CD56 嵌合抗原受体表达 T 细胞，以及 DNA 损伤修复抑制。
YAP1 定义了具有独特生物学特性的 LCNEC 不同亚组。这些发现强调了 YAP1 指导 LCNEC 个性化治疗策略的潜力。
