Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints.Preclinical data indicate that targeting of histone-lysine N-methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaete-scute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody–drug conjugate. The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1). Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status. Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients.

中文翻译：

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揭开 SCLC 的生物学原理：对治疗的影响

小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，预后不良。一线治疗几十年来一直保持不变，并且针对复发性疾病缺乏有效的治疗选择。尽管如此，我们对 SCLC 生物学理解的进步促进了新型实验疗法的发展。聚[ADP-核糖]聚合酶（PARP）抑制剂在临床前模型中显示出前景，并且正在与细胞毒性疗法和细胞周期检查点抑制剂联合进行临床研究。临床前数据表明，靶向组蛋白赖氨酸N-甲基转移酶EZH2，与获得性治疗耐药有关的染色质重塑调节因子，可能会增强和延长化疗反应。大多数 SCLC 中抑制性 Notch 配体 Delta 样蛋白 3 (DLL3) 的高表达与 Achaete-scute 同源物 1 (ASCL1；也称为 ASH-1) 的表达有关，后者是驱动 SCLC 肿瘤发生的关键转录因子；抗 DLL3-抗体-药物偶联物已被证明具有令人鼓舞的临床前和临床活性。SCLC 的免疫微环境似乎与其他实体瘤不同，肿瘤浸润淋巴细胞很少，免疫检查点蛋白程序性细胞死亡 1 配体 1 (PD-L1) 水平较低。尽管如此，免疫检查点抑制剂的免疫疗法为患有这种疾病的患者带来了希望，而与 PD-L1 状态无关。在此，我们回顾了在揭示 SCLC 生物学及其微环境方面所取得的进展，这些进展正在定义新的治疗策略并为患者带来新的希望。