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：

---

揭示SCLC的生物学：对治疗的意义

小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，预后不良。一线治疗数十年来一直保持不变，并且对于复发性疾病缺乏有效的治疗选择。尽管如此，我们对SCLC生物学的理解的进步导致了新型实验疗法的发展。聚[ADP-核糖]聚合酶（PARP）抑制剂已在临床前模型中显示出希望，并且正在与细胞毒性疗法和细胞周期检查点抑制剂结合进行临床研究。临床前数据表明，靶向组蛋白-赖氨酸N-甲基转移酶EZH2是染色质重塑的调节因子，可能与获得性治疗耐药有关，可能会增强并延长化疗反应。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，Achaete-scute同源物1是驱动SCLC发生的关键转录因子。抗DLL3抗体-药物偶联物已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肿瘤不同，肿瘤浸润淋巴细胞少，免疫检查点蛋白编程的细胞死亡1配体1（PD-L1）水平低。但是，与PD-L1状态无关，使用免疫检查点抑制剂的免疫疗法有望使患有这种疾病的患者受益。