Novel therapeutic combinations with PARP inhibitors for small cell lung cancer: A bench-to-bedside review.
Novel therapeutic combinations with PARP inhibitors for small cell lung cancer: A bench-to-bedside review.
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DOI：
10.1016/j.semcancer.2022.07.008
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发表时间：
2022-07
影响因子：
14.5
通讯作者：
Jiaqi Xiong;R. Barayan;A. Louie;B. Lok
中科院分区：
文献类型：
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作者：
Jiaqi Xiong;R. Barayan;A. Louie;B. Lok
尽管小细胞肺癌（SCLC）具有明显的肿瘤内和肿瘤间异质性，但仍被视为一种整体性疾病。几十年来，非特异性 DNA 损伤剂一直是一线治疗方法。最近，新兴的 SCLC 肿瘤转录组学和基因组分析发现了不同的 SCLC 亚型和靶向治疗的脆弱性，包括核酶聚（ADP-核糖）聚合酶（PARPi）的抑制剂。与健康肺组织和其他肺肿瘤亚型相比，SCLC 细胞系和肿瘤表现出 PARP1 蛋白和 mRNA 水平升高。在临床前 SCLC 模型中也观察到对 PARPi 的显着反应。临床上，PARPi 单一疗法对 SCLC 患者产生了不同的益处。迄今为止，人们正在大力开展研究，以检查 PARPi 反应的预测生物标志物和各种 PARPi 组合策略，以最大限度地发挥 PARPi 的临床效用。这篇叙述性综述总结了支持 PARPi 单一疗法、联合疗法以及各自临床转化的现有临床前证据。具体来说，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）以及许多其他针对 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组合。还讨论了假定的生物标志物，例如 SLFN11 表达、MGMT 甲基化、E2F1 表达和铂敏感性，它们可能预测对不同治疗组合的反应。 SCLC 治疗的未来正在经历快速变化，重点是量身定制和个性化的治疗策略。 PARPi 癌症治疗的进一步发展将极大地惠及至少一部分生物标志物定义的 SCLC 患者。
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 asSLFN11expression,MGMTmethylation,E2F1expression, 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.