Lee Ji Hae, Kwon Youngjoo, Yoon Kyungsil
Cancer Metastasis Branch, National Cancer Center, Goyang 10408, Korea.
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
Int J Biol Sci. 2025 Jul 28;21(11):4851-4871. doi: 10.7150/ijbs.109419. eCollection 2025.
Platinum-based chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC); however, innate and acquired resistance is a major obstacle. To determine the transcriptional regulators of resistance, we first classified three-dimensional tumor spheroids derived from 11 NSCLC cell lines into cisplatin-sensitive or -resistant groups based on their cisplatin sensitivity and selected signature genes that were differentially altered between the groups. Using reverse engineering methods and functional validation, cAMP response element-binding protein 1 (CREB) was identified as a major regulator of cisplatin resistance. Among the putative target genes of CREB responsible for cisplatin resistance, cisplatin treatment significantly decreased the occupancy of CREB in the regulatory regions of and in cisplatin-sensitive cells, but not in resistant cells, resulting in decreased expression of these protein in the sensitive group. Furthermore, CREB knockdown led to increased sensitivity to cisplatin with reduced levels of TNKS and KDM6A in both cisplatin-resistant tumor spheroids and tumors in a xenograft mouse model. In conclusion, our study delineates the role of CREB in cisplatin resistance and suggests that CREB inhibition is a potential therapeutic strategy for cisplatin-resistant NSCLCs.
铂类化疗是晚期非小细胞肺癌（NSCLC）的标准治疗方法；然而，固有耐药和获得性耐药是一个主要障碍。为了确定耐药的转录调节因子，我们首先根据顺铂敏感性将源自11种NSCLC细胞系的三维肿瘤球体分为顺铂敏感组或耐药组，并选择了两组之间差异改变的特征基因。通过逆向工程方法和功能验证，环磷酸腺苷反应元件结合蛋白1（CREB）被确定为顺铂耐药的主要调节因子。在负责顺铂耐药的CREB假定靶基因中，顺铂处理显著降低了CREB在顺铂敏感细胞中 和 调控区域的占有率，但在耐药细胞中没有降低，导致这些蛋白在敏感组中的表达降低。此外，在顺铂耐药肿瘤球体和异种移植小鼠模型的肿瘤中，CREB敲低导致对顺铂的敏感性增加，同时TNKS和KDM6A水平降低。总之，我们的研究阐述了CREB在顺铂耐药中的作用，并表明抑制CREB是顺铂耐药NSCLC的一种潜在治疗策略。
