Emerging advances in defining the molecular and therapeutic landscape of small-cell lung cancer
(Nature Reviews Clinical Oncology, IF: 81.1)
Triparna Sen, Nobuyuki Takahashi, Subhamoy Chakraborty, Naoko Takebe, Amin H. Nassar, Nagla A. Karim, Sonam Puri & Abdul Rafeh Naqash
CORRESPONDENCE TO: [email protected]; [email protected]
Small-cell lung cancer (SCLC) has traditionally been considered a recalcitrant cancer with a dismal prognosis, with only modest advances in therapeutic strategies over the past several decades. Comprehensive genomic assessments of SCLC have revealed that most of these tumours harbour deletions of the tumour-suppressor genes TP53 and RB1 but, in contrast to non-small-cell lung cancer, have failed to identify targetable alterations. The expression status of four transcription factors with key roles in SCLC pathogenesis defines distinct molecular subtypes of the disease, potentially enabling specific therapeutic approaches. Overexpression and amplification of MYC paralogues also affect the biology and therapeutic vulnerabilities of SCLC. Several other attractive targets have emerged in the past few years, including inhibitors of DNA-damage-response pathways, epigenetic modifiers, antibody– drug conjugates and chimeric antigen receptor T cells. However, the rapid development of therapeutic resistance and lack of biomarkers for effective selection of patients with SCLC are ongoing challenges. Emerging single-cell RNA sequencing data are providing insights into the plasticity and intratumoural and intertumoural heterogeneity of SCLC that might be associated with therapeutic resistance. In this Review, we provide a comprehensive overview of the latest advances in genomic and transcriptomic characterization of SCLC with a particular focus on opportunities for translation into new therapeutic approaches to improve patient outcomes.
小细胞肺癌（SCLC）传统上被认为是一种顽固的癌症，预后极差，在过去几十年中，治疗策略只有适度的进步。SCLC的全面基因组评估显示，这些肿瘤中的大多数含有肿瘤抑制基因TP53和RB1的缺失，但与非小细胞肺癌相比，未能确定靶向性改变。在小细胞肺癌发病机制中起关键作用的四种转录因子的表达状态定义了该疾病的不同分子亚型，使特定的治疗方法成为可能。MYC同源物的过表达和扩增也会影响小细胞肺癌的生物学特质和治疗脆弱性。在过去几年中，出现了其他几个有吸引力的靶点，包括DNA损伤反应途径的抑制剂、表观遗传修饰剂、抗体-药物偶联物和嵌合抗原受体T细胞。然而，治疗耐药性的快速发展和缺乏有效选择小细胞肺癌患者的生物标志物是持续的挑战。新兴的单细胞RNA测序数据为小细胞肺癌的可塑性、瘤内和瘤间异质性提供了见解，这些异质性可能与治疗耐药性有关。在本综述中，我们全面概述了小细胞肺癌基因组和转录组特征的最新进展，特别关注可转化为新治疗方法以改善患者预后的机会。
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