IκBα kinase inhibitor BAY 11-7082 promotes anti-tumor effect in RAS-driven cancers

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.

Conclusion: 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.

HRAS; KRAS; MAPK; NRAS; PI3K-AKT.