Reference Detail

Ref Type

Journal Article

PMID

(38982514)

Authors

Guruvaiah P, Gupta R

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of translational medicine	22	1	2024 Jul 09	642	J Transl Med

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
HRAS act mut	Advanced Solid Tumor	predicted - sensitive	BAY 11-7082	Preclinical - Cell line xenograft	Actionable	In a preclinical study, BAY 11-7082 induced apoptosis and decreased Akt signaling, viability, and colony formation in cancer cells harboring activating HRAS mutations in culture and inhibited tumor growth in a cell line xenograft model (PMID: 38982514).	38982514
NRAS act mut	melanoma	sensitive	BAY 11-7082	Preclinical - Cell line xenograft	Actionable	In a preclinical study, BAY 11-7082 induced apoptosis and decreased Akt signaling, viability, and colony formation in melanoma cell lines harboring activating NRAS mutations in culture and inhibited tumor growth in a cell line xenograft model (PMID: 38982514).	38982514