RAS 基因的致癌突变与不受控制的细胞生长有关，这是导致肿瘤发生的一个标志性特征。尽管多种治疗策略已被广泛应用于治疗 RAS 突变癌症，但成功靶向 RAS 基因仍然是癌症治疗领域的一个持续挑战。在我们的研究中，我们发现了解决这一挑战的有希望的途径。在这项研究中，我们测试了几种携带致癌 NRAS、KRAS 和 HRAS 突变的细胞系在用 IkappaBalpha (IκBα) 抑制剂 BAY 11-7082 治疗后的活力。我们进行了基于细胞培养的活力测定和基于体内皮下异种移植的测定，以确认 BAY 11-7082 的生长抑制作用。我们还进行了大 RNA 测序分析，以确定在使用 BAY 11-7082 治疗后，致癌 NRAS、KRAS 和 HRAS 突变背景下的差异调节基因和通路。我们证明，致癌 NRAS、KRAS 和 HRAS 激活 IκBα 激酶的表达。 BAY 11-7082 是一种 IκBα 激酶抑制剂，可减弱细胞培养物和小鼠模型中 NRAS、KRAS 和 HRAS 突变癌细胞的生长。从机制上讲，BAY 11-7082 抑制剂治疗可抑制所有 RAS 突变细胞系中的 PI3K-AKT 信号通路并激活细胞凋亡。此外，我们发现 BAY 11-7082 治疗会导致不同生物途径的下调，具体取决于 RAS 蛋白的类型，这也可能有助于抑制肿瘤生长。我们的研究确定 BAY 11-7082 是治疗 RAS 癌基因的有效抑制剂（HRAS、KRAS 和 NRAS）突变癌细胞。这一发现为有效治疗 RAS 突变癌症提供了新的治疗机会。© 2024。作者。

Oncogenic mutations in the RAS gene are associated with uncontrolled cell growth, a hallmark feature contributing to tumorigenesis. While diverse therapeutic strategies have been diligently applied to treat RAS-mutant cancers, successful targeting of the RAS gene remains a persistent challenge in the field of cancer therapy. In our study, we discover a promising avenue for addressing this challenge.In this study, we tested the viability of several cell lines carrying oncogenic NRAS, KRAS, and HRAS mutations upon treatment with IkappaBalpha (IκBα) inhibitor BAY 11-7082. We performed both cell culture-based viability assay and in vivo subcutaneous xenograft-based assay to confirm the growth inhibitory effect of BAY 11-7082. We also performed large RNA sequencing analysis to identify differentially regulated genes and pathways in the context of oncogenic NRAS, KRAS, and HRAS mutations upon treatment with BAY 11-7082.We demonstrate that oncogenic NRAS, KRAS, and HRAS activate the expression of IκBα kinase. BAY 11-7082, an inhibitor of IκBα kinase, attenuates the growth of NRAS, KRAS, and HRAS mutant cancer cells in cell culture and in mouse model. Mechanistically, BAY 11-7082 inhibitor treatment leads to suppression of the PI3K-AKT signaling pathway and activation of apoptosis in all RAS mutant cell lines. Additionally, we find that BAY 11-7082 treatment results in the downregulation of different biological pathways depending upon the type of RAS protein that may also contribute to tumor growth inhibition.Our study identifies BAY 11-7082 to be an efficacious inhibitor for treating RAS oncogene (HRAS, KRAS, and NRAS) mutant cancer cells. This finding provides new therapeutic opportunity for effective treatment of RAS-mutant cancers.© 2024. The Author(s).