KEAP1/NRF2 通路是多个氧化还原敏感基因的主要调节因子，这些基因与肿瘤细胞对治疗药物的耐药性有关。 KEAP1/NRF2 系统的功能障碍与肿瘤患者的预后和对常规疗法的反应相关。在肺部肿瘤中，癌细胞的生长和进展也可能涉及分子 NRF2/KEAP1 轴与其他通路（包括 NOTCH）之间的交叉，这对抗氧化保护、癌细胞存活和治疗耐药性具有影响。目前，有关 SCLC 异常 NRF2/NOTCH 串扰机制及其遗传和表观遗传基础的数据尚不完整。为了更好地阐明这一点并阐明 NRF2/NOTCH 串扰失调在 SCLC 肿瘤发生中的作用，我们研究了 SCLC 细胞系子集中 KEAP1 基因的遗传和表观遗传功能障碍。此外，我们评估了它对 SCLC 细胞对传统化疗（依托泊苷、顺铂及其组合）和使用 DAPT（一种 γ-分泌酶抑制剂 (GSI)）的 NOTCH 抑制剂治疗的反应的影响。我们证明，KEAP1/NRF2 轴在 SCLC 细胞系中受到表观遗传控制，并且 siRNA 沉默 KEAP1 会诱导 NRF2 上调，从而增加 SCLC 细胞在顺铂和依托泊苷治疗下的化疗耐药性。此外，KEAP1 调节还干扰 NOTCH1、HES1 和 DLL3 转录。我们的初步数据提供了有关 KEAP1 功能障碍对此类肿瘤中 NRF2 和 NOTCH 失调的下游影响的新见解，并证实了这两种途径在 SCLC 肿瘤发生中协同作用的假设。

The KEAP1/NRF2 pathway is a master regulator of several redox-sensitive genes implicated in the resistance of tumor cells against therapeutic drugs. The dysfunction of the KEAP1/NRF2 system has been correlated with neoplastic patients' outcomes and responses to conventional therapies. In lung tumors, the growth and the progression of cancer cells may also involve the intersection between the molecular NRF2/KEAP1 axis and other pathways, including NOTCH, with implications for antioxidant protection, survival of cancer cells, and drug resistance to therapies. At present, the data concerning the mechanism of aberrant NRF2/NOTCH crosstalk as well as its genetic and epigenetic basis in SCLC are incomplete. To better clarify this point and elucidate the contribution of NRF2/NOTCH crosstalk deregulation in tumorigenesis of SCLC, we investigated genetic and epigenetic dysfunctions of the KEAP1 gene in a subset of SCLC cell lines. Moreover, we assessed its impact on SCLC cells' response to conventional chemotherapies (etoposide, cisplatin, and their combination) and NOTCH inhibitor treatments using DAPT, a γ-secretase inhibitor (GSI). We demonstrated that the KEAP1/NRF2 axis is epigenetically controlled in SCLC cell lines and that silencing of KEAP1 by siRNA induced the upregulation of NRF2 with a consequent increase in SCLC cells' chemoresistance under cisplatin and etoposide treatment. Moreover, KEAP1 modulation also interfered with NOTCH1, HES1, and DLL3 transcription. Our preliminary data provide new insights about the downstream effects of KEAP1 dysfunction on NRF2 and NOTCH deregulation in this type of tumor and corroborate the hypothesis of a cooperation of these two pathways in the tumorigenesis of SCLC.