Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Semin Cancer Biol. 2022 Nov;86(Pt 2):521-542. doi: 10.1016/j.semcancer.2022.07.008. Epub 2022 Jul 30.
Small cell lung cancer (SCLC) is treated as a monolithic disease despite the evident intra- and intertumoral heterogeneity. Non-specific DNA-damaging agents have remained the first-line treatment for decades. Recently, emerging transcriptomic and genomic profiling of SCLC tumors identified distinct SCLC subtypes and vulnerabilities towards targeted therapeutics, including inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARPi). SCLC cell lines and tumors exhibited an elevated level of PARP1 protein and mRNA compared to healthy lung tissues and other subtypes of lung tumors. Notable responses to PARPi were also observed in preclinical SCLC models. Clinically, PARPi monotherapy exerted variable benefits for SCLC patients. To date, research is being vigorously conducted to examine predictive biomarkers of PARPi response and various PARPi combination strategies to maximize the clinical utility of PARPi. This narrative review summarizes existing preclinical evidence supporting PARPi monotherapy, combination therapy, and respective translation to the clinic. Specifically, we covered the combination of PARPi with DNA-damaging chemotherapy (cisplatin, etoposide, temozolomide), thoracic radiotherapy, immunotherapy (immune checkpoint inhibitors), and many other novel therapeutic agents that target DNA damage response, tumor microenvironment, epigenetic modulation, angiogenesis, the ubiquitin-proteasome system, or autophagy. Putative biomarkers, such as SLFN11 expression, MGMT methylation, E2F1 expression, and platinum sensitivity, which may be predictive of response to distinct therapeutic combinations, were also discussed. The future of SCLC treatment is undergoing rapid change with a focus on tailored and personalized treatment strategies. Further development of cancer therapy with PARPi will immensely benefit at least a subset of biomarker-defined SCLC patients.
小细胞肺癌 (SCLC) 尽管存在明显的肿瘤内和肿瘤间异质性，但仍被视为一种单一疾病进行治疗。几十年来，非特异性 DNA 损伤剂一直是一线治疗方法。最近，对 SCLC 肿瘤的转录组和基因组分析表明，存在不同的 SCLC 亚型和针对靶向治疗的脆弱性，包括聚（ADP-核糖）聚合酶（PARPi）的核酶抑制剂。与健康肺组织和其他类型的肺癌肿瘤相比，SCLC 细胞系和肿瘤表现出更高水平的 PARP1 蛋白和 mRNA。在临床前 SCLC 模型中也观察到了对 PARPi 的显著反应。临床上，PARPi 单药治疗对 SCLC 患者有不同程度的获益。迄今为止，研究人员正在大力研究 PARPi 反应的预测生物标志物以及各种 PARPi 联合治疗策略，以最大程度地提高 PARPi 的临床应用价值。本文综述了支持 PARPi 单药治疗、联合治疗以及各自向临床转化的现有临床前证据。具体而言，我们涵盖了 PARPi 与 DNA 损伤化疗（顺铂、依托泊苷、替莫唑胺）、胸部放疗、免疫疗法（免疫检查点抑制剂）以及许多其他靶向 DNA 损伤反应、肿瘤微环境、表观遗传调节、血管生成、泛素-蛋白酶体系统或自噬的新型治疗药物的联合治疗。还讨论了可能具有预测价值的生物标志物，如 SLFN11 表达、MGMT 甲基化、E2F1 表达和铂类敏感性，这些生物标志物可能预测对不同治疗组合的反应。SCLC 治疗的未来正在发生快速变化，重点是制定个性化的治疗策略。进一步开发 PARPi 癌症疗法将使至少一部分具有生物标志物定义的 SCLC 患者受益匪浅。
