YAP1 状态定义了 LCNEC 的两种内在亚型,它们具有不同的分子特征和治疗弱点。

IF 10 1区 医学 Q1 ONCOLOGY
C Allison Stewart, Lixia Diao, Yuanxin Xi, Runsheng Wang, Kavya Ramkumar, Alejandra G Serrano, Azusa Tanimoto, B Leticia Rodriguez, Benjamin B Morris, Li Shen, Bingnan Zhang, Yan Yang, Samera H Hamad, Robert J Cardnell, Alberto Duarte, Moushumi Sahu, Veronica Y Novegil, Bernard E Weissman, Michael Frumovitz, Neda Kalhor, Luisa Solis Soto, Pedro da Rocha, Natalie Vokes, Don L Gibbons, Jing Wang, John V Heymach, Bonnie Glisson, Lauren Averett Byers, Carl M Gay
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引用次数: 0

摘要

目的: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,缺乏可药物治疗的致癌驱动因素,预后不良。然而,与小细胞肺癌相比,目前几乎没有证据可以指导最佳治疗策略,这些策略通常是根据小细胞肺癌和非小细胞肺癌(NSCLC)的方法调整而来:为了更好地确定 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组织进行了免疫组化和单细胞 (sc)RNAseq 分析:结果:我们在此证明,YAP1 的存在与否可区分 LCNEC 的两个亚群。YAP1高的亚组是间质和炎症亚组,其特征是CDKN2A/B和SMARCA4同时发生突变,TP53也发生突变。在治疗上,YAP1-高亚群易受MEK和AXL靶向策略的影响,包括一种新型临床前AXL CAR-T细胞。同时,YAP1-低亚群具有上皮性和免疫冷冻性,更常见的特征是TP53和RB1共突变,这与在纯合SCLC中观察到的特征相似。值得注意的是,YAP1-low亚群的特征还包括表达SCLC亚型定义的转录因子--特别是ASCL1和NEUROD1--而且,正如预期的那样,由于其转录与SCLC相似,YAP1-low亚群表现出与SCLC相似的潜在脆弱性,包括Delta样配体3(DLL3)和CD56靶向(如临床前新型DLL3和CD56 CAR T细胞)以及DNA损伤修复(DDR)抑制:结论:YAP1定义了具有独特生物学特性的LCNEC不同亚群。这些发现凸显了 YAP1 引导 LCNEC 个性化治疗策略的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
YAP1 Status Defines Two Intrinsic Subtypes of LCNEC with Distinct Molecular Features and Therapeutic Vulnerabilities.

Purpose: 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.

Experimental design: 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.

Results: 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.

Conclusions: YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC.

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来源期刊
Clinical Cancer Research
Clinical Cancer Research 医学-肿瘤学
CiteScore
20.10
自引率
1.70%
发文量
1207
审稿时长
2.1 months
期刊介绍: Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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