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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：RAS基因的致癌突变与不受控制的细胞生长有关，有助于肿瘤发生的标志特征。虽然不同的治疗策略已经努力应用于治疗RAS突变癌症，成功靶向RAS基因仍然是癌症治疗领域的持续挑战.在我们的研究中,我们发现了一个有希望的途径来应对这一挑战。
方法：在本研究中，我们测试了几种携带致癌NRAS的细胞系的活力，KRAS,和用IkappaBalpha(IκBα)抑制剂BAY11-7082治疗后的HRAS突变。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物的测定,以证实BAY11-7082的生长抑制作用。我们还进行了大型RNA测序分析，以确定在致癌NRAS的背景下差异调节的基因和途径。KRAS,和用BAY11-7082治疗后的HRAS突变。
结果：我们证明了致癌NRAS，KRAS,HRAS激活IκBα激酶的表达。BAY11-7082,IκBα激酶抑制剂,减弱NRAS的生长，KRAS,细胞培养和小鼠模型中的HRAS突变癌细胞。机械上,BAY11-7082抑制剂处理导致所有RAS突变细胞系中PI3K-AKT信号传导途径的抑制和细胞凋亡的激活。此外,我们发现BAY11-7082治疗会导致不同生物学途径的下调，这取决于RAS蛋白的类型，这也可能有助于肿瘤生长抑制。
结论：我们的研究确定BAY11-7082是治疗RAS癌基因的有效抑制剂（HRAS，KRAS,和NRAS）突变的癌细胞。这一发现为有效治疗RAS突变癌症提供了新的治疗机会。
方法：在本研究中，我们测试了几种携带致癌NRAS的细胞系的活力，KRAS,和用IkappaBalpha(IκBα)抑制剂BAY11-7082治疗后的HRAS突变。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物的测定,以证实BAY11-7082的生长抑制作用。我们还进行了大型RNA测序分析，以确定在致癌NRAS的背景下差异调节的基因和途径。KRAS,和用BAY11-7082治疗后的HRAS突变。
结果：我们证明了致癌NRAS，KRAS,HRAS激活IκBα激酶的表达。BAY11-7082,IκBα激酶抑制剂,减弱NRAS的生长，KRAS,细胞培养和小鼠模型中的HRAS突变癌细胞。机械上,BAY11-7082抑制剂处理导致所有RAS突变细胞系中PI3K-AKT信号传导途径的抑制和细胞凋亡的激活。此外,我们发现BAY11-7082治疗会导致不同生物学途径的下调，这取决于RAS蛋白的类型，这也可能有助于肿瘤生长抑制。
结论：我们的研究确定BAY11-7082是治疗RAS癌基因的有效抑制剂（HRAS，KRAS,和NRAS）突变的癌细胞。这一发现为有效治疗RAS突变癌症提供了新的治疗机会。
