Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, Netherlands.
Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
Semin Cancer Biol. 2022 Nov;86(Pt 2):376-385. doi: 10.1016/j.semcancer.2022.05.004. Epub 2022 May 11.
Small cell lung cancer (SCLC) arises in peribronchial locations and infiltrates the bronchial submucosa, including about 15% of lung cancer cases. Despite decades of research, the prognosis for SCLC patients remains poor because this tumor is characterized by an exceptionally high proliferative rate, strong tendency for early widespread metastasis and acquired chemoresistance. Omics profiling revealed that SCLC harbor extensive chromosomal rearrangements and a very high mutation burden. This led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy, which however resulted in a prolonged benefit only for a small subset of patients. Thus, the present review discusses the rationale and limitations of immunotherapeutic approaches, presenting the current biological understanding of aberrant signaling pathways that might be exploited with new potential treatments. In particular, new agents targeting DNA damage repair, cell cycle checkpoint, and apoptosis pathways showed several promising results in different preclinical models. Epigenetic alterations, gene amplifications and mutations can act as biomarkers in this context. Future research and improved clinical outcome for SCLC patients will depend on the integration between these omics and pharmacological studies with clinical translational research, in order to identify specific predictive biomarkers that will be hopefully validated using clinical trials with biomarker-selected targeted treatments.
小细胞肺癌（SCLC）起源于支气管周围部位并浸润支气管黏膜下层，约占肺癌病例的 15%。尽管经过几十年的研究，SCLC 患者的预后仍然很差，因为这种肿瘤的特点是增殖率极高、早期广泛转移的强烈趋势和获得性化疗耐药性。组学分析显示，SCLC 存在广泛的染色体重排和极高的突变负担。这导致了免疫检查点抑制剂作为单一药物或与化疗联合使用的发展，但这仅为一小部分患者带来了延长的益处。因此，本综述讨论了免疫治疗方法的原理和局限性，介绍了目前对异常信号通路的生物学理解，这些通路可能可以通过新的潜在治疗方法加以利用。特别是，针对 DNA 损伤修复、细胞周期检查点和细胞凋亡通路的新药物在不同的临床前模型中显示出了一些有前途的结果。在这种情况下，表观遗传改变、基因扩增和突变可以作为生物标志物。未来的研究和 SCLC 患者的临床转归将取决于这些组学与临床转化研究之间的整合，以便确定特定的预测性生物标志物，希望通过针对生物标志物选择的临床试验进行验证。
