Current treatment guidelines refer to small cell lung cancer (SCLC), one of the deadliest human malignancies, as a homogeneous disease. Accordingly, SCLC therapy comprises chemoradiation with or without immunotherapy. Meanwhile, recent studies have made significant advances in subclassifying SCLC based on the elevated expression of the transcription factors ASCL1, NEUROD1, and POU2F3, as well as on certain inflammatory characteristics. The role of the transcription regulator YAP1 in defining a unique SCLC subset remains to be established. Although preclinical analyses have described numerous subtype-specific characteristics and vulnerabilities, the so far non-existing clinical subtype distinction may be a contributor to negative clinical trial outcomes. This comprehensive review aims to provide a framework for the development of novel personalized therapeutic approaches by compiling the most recent discoveries achieved by preclinical SCLC research. We highlight the challenges faced due to limited access to patient material as well as the advances accomplished by implementing state-of-the-art models and methodologies.

中文翻译：

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小细胞——大问题：小细胞肺癌的生物学意义和临床前进展

目前的治疗指南将小细胞肺癌（SCLC）（人类最致命的恶性肿瘤之一）视为一种同质疾病。因此，SCLC治疗包括放化疗联合或不联合免疫治疗。与此同时，最近的研究在基于转录因子 ASCL1、NEUROD1 和 POU2F3 表达升高以及某些炎症特征的 SCLC 亚分类方面取得了重大进展。转录调节因子 YAP1 在定义独特的 SCLC 亚群中的作用仍有待确定。尽管临床前分析描述了许多亚型特异性特征和脆弱性，但迄今为止不存在的临床亚型区别可能是导致负面临床试验结果的一个因素。这篇全面的综述旨在通过汇编临床前 SCLC 研究取得的最新发现，为新型个性化治疗方法的开发提供一个框架。我们强调了由于获取患者材料有限而面临的挑战，以及通过实施最先进的模型和方法所取得的进步。