Institute for Genetics, University of Cologne, 50674, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.
Cell Death Differ. 2023 Apr;30(4):938-951. doi: 10.1038/s41418-023-01112-5. Epub 2023 Jan 18.
Small cell lung cancer (SCLC) is an aggressive type of lung cancer driven by combined loss of the tumor suppressors RB1 and TP53. SCLC is highly metastatic and despite good initial response to chemotherapy patients usually relapse, resulting in poor survival. Therefore, better understanding of the mechanisms driving SCLC pathogenesis is required to identify new therapeutic targets. Here we identified a critical role of the IKK/NF-κB signaling pathway in SCLC development. Using a relevant mouse model of SCLC, we found that ablation of NEMO/IKKγ, the regulatory subunit of the IKK complex that is essential for activation of canonical NF-κB signaling, strongly delayed the onset and growth of SCLC resulting in considerably prolonged survival. In addition, ablation of the main NF-κB family member p65/RelA also delayed the onset and growth of SCLC and prolonged survival, albeit to a lesser extent than NEMO. Interestingly, constitutive activation of IKK/NF-κB signaling within the tumor cells did not exacerbate the pathogenesis of SCLC, suggesting that endogenous NF-κB levels are sufficient to fully support tumor development. Moreover, TNFR1 deficiency did not affect the development of SCLC, showing that TNF signaling does not play an important role in this tumor type. Taken together, our results revealed that IKK/NF-κB signaling plays an important role in promoting SCLC, identifying the IKK/NF-κB pathway as a promising therapeutic target.
小细胞肺癌（SCLC）是一种侵袭性肺癌，由肿瘤抑制因子 RB1 和 TP53 的联合缺失驱动。SCLC具有高度转移性，尽管对化疗有良好的初始反应，但患者通常会复发，导致生存状况不佳。因此，需要更好地了解驱动 SCLC 发病机制的机制，以确定新的治疗靶点。在这里，我们发现 IKK/NF-κB 信号通路在 SCLC 发展中起着关键作用。使用相关的 SCLC 小鼠模型，我们发现，IKK 复合物的调节亚基 NEMO/IKKγ的缺失强烈延迟了 SCLC 的发生和生长，导致生存率显著延长。此外，主要的 NF-κB 家族成员 p65/RelA 的缺失也延迟了 SCLC 的发生和生长，并延长了生存时间，但程度不如 NEMO 明显。有趣的是，肿瘤细胞内 IKK/NF-κB 信号的组成性激活并没有加剧 SCLC 的发病机制，表明内源性 NF-κB 水平足以完全支持肿瘤的发展。此外，TNFR1 的缺失并不影响 SCLC 的发生，表明 TNF 信号在这种肿瘤类型中不起重要作用。总之，我们的结果表明，IKK/NF-κB 信号在促进 SCLC 中起着重要作用，确定 IKK/NF-κB 途径是一个有前途的治疗靶点。
