Targeting Hippo signaling in cancer: novel perspectives and therapeutic potential

Lv, Liemei; Zhou, Xiangxiang

doi:10.1002/mco2.375

Cited by 7 publications

(4 citation statements)

References 261 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HIF-1 signaling activates the transcription of crucial genes involved in tumor growth [ 51 ]. Prolactin signaling via Janus kinase-signal transducer and activator of transcription (JAK-STAT) is shown to promote tumor growth [ 52 ] and the Hippo pathway regulates metabolic reprogramming to promote the growth of malignant tumors [ 53 ]. These results highlight that many important pathways downregulated by BAY 11-7082 treatment impair the development of NRAS, KRAS, and HRAS mutant cancer.…”

Section: Discussionmentioning

confidence: 99%

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

Guruvaiah,

Gupta

2024

J Transl Med

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Guruvaiah,

Gupta

2024

J Transl Med

View full text Add to dashboard Cite

show abstract

“…These proteins phosphorylate YAP and TAZ, tagging them for cytoplasmic degradation and preventing their nuclear translocation, thus inhibiting transcription via TEADs and SMADs. Activation occurs through FAT1, KIBRA, AJUBA, NF2, RHO, AMPK, or by inactivation of STRIPAK complexes, which regulate MST1/2 and MAP4Ks ( 189 , 190 ). In head and neck squamous cell carcinoma, common aberrations include mutations in FAT1, WWTR1/TAZ, YAP1, and MST2 ( 191 , 192 ).…”

Section: Hnc Molecular Pathogenesismentioning

confidence: 99%

“…Since 2016, several molecules targeting the Hippo pathway have been developed. In nasopharyngeal carcinoma, MGH-CP1, an inhibitor of TEAD2/4 auto-palmitoylation, is in preclinical trials, reducing TEAD4-mediated AKT signaling and inhibiting cell migration, invasion, and resistance to cisplatin ( 50 , 189 ).…”

Section: Hnc Molecular Pathogenesismentioning

confidence: 99%

Molecular pathways and targeted therapies in head and neck cancers pathogenesis

Constantin,

Chifiriuc,

Bleotu

et al. 2024

Front. Oncol.

View full text Add to dashboard Cite

The substantial heterogeneity exhibited by head and neck cancer (HNC), encompassing diverse cellular origins, anatomical locations, and etiological contributors, combined with the prevalent late-stage diagnosis, poses significant challenges for clinical management. Genomic sequencing endeavors have revealed extensive alterations in key signaling pathways that regulate cellular proliferation and survival. Initiatives to engineer therapies targeting these dysregulated pathways are underway, with several candidate molecules progressing to clinical evaluation phases, including FDA approval for agents like the EGFR-targeting monoclonal antibody cetuximab for K-RAS wild-type, EGFR-mutant HNSCC treatment. Non-coding RNAs (ncRNAs), owing to their enhanced stability in biological fluids and their important roles in intracellular and intercellular signaling within HNC contexts, are now recognized as potent biomarkers for disease management, catalyzing further refined diagnostic and therapeutic strategies, edging closer to the personalized medicine desideratum. Enhanced comprehension of the genomic and immunological landscapes characteristic of HNC is anticipated to facilitate a more rigorous assessment of targeted therapies benefits and limitations, optimize their clinical deployment, and foster innovative advancements in treatment approaches. This review presents an update on the molecular mechanisms and mutational spectrum of HNC driving the oncogenesis of head and neck malignancies and explores their implications for advancing diagnostic methodologies and precision therapeutics.

show abstract

“…Wei and his colleagues found that verteporfin suppresses proliferation, migration, and invasion of EC cells that are resistant to conventional progestin-based therapy [ 29 ]. Another YAP-transcriptional suppressor, Vestigial-like-4 (VGLL-4), has also recently emerged as a novel tumour suppressor in colon cancer by regulating both the YAP/TAZ and β-catenin-TCF4 complex [ 30 ]. This was highlighted by Jiao and his team in a study published in 2017 that reported VGLL4 peptide mimics suppress CRC tumour growth by interfering with the transactivation of YAP/TAZ and the β-catenin/TCF4 complex, thereby preventing the constitutive transcription of WNT and Hippo oncogenic target genes.…”

Section: Introductionmentioning

confidence: 99%

Drug Repurposing: Exploring Potential Anti-Cancer Strategies by Targeting Cancer Signalling Pathways

Haddad,

Gamaethige,

Wehida

et al. 2024

Biology

View full text Add to dashboard Cite

The repurposing of previously clinically approved drugs as an alternative therapeutic approach to treating disease has gained significant attention in recent years. A multitude of studies have demonstrated various and successful therapeutic interventions with these drugs in a wide range of neoplastic diseases, including multiple myeloma, leukaemia, glioblastoma, and colon cancer. Drug repurposing has been widely encouraged due to the known efficacy, safety, and convenience of already established drugs, allowing the bypass of the long and difficult road of lead optimization and drug development. Repurposing drugs in cancer therapy is an exciting prospect due to the ability of these drugs to successfully target cancer-associated genes, often dysregulated in oncogenic signalling pathways, amongst which are the classical cancer signalling pathways; WNT (wingless-related integration type) and Hippo signalling. These pathways play a fundamental role in controlling organ size, tissue homeostasis, cell proliferation, and apoptosis, all hallmarks of cancer initiation and progression. Prolonged dysregulation of these pathways has been found to promote uncontrolled cellular growth and malignant transformation, contributing to carcinogenesis and ultimately leading to malignancy. However, the translation of cancer signalling pathways and potential targeted therapies in cancer treatment faces ongoing challenges due to the pleiotropic nature of cancer cells, contributing to resistance and an increased rate of incomplete remission in patients. This review provides analyses of a range of potential anti-cancer compounds in drug repurposing. It unravels the current understanding of the molecular rationale for repurposing these drugs and their potential for targeting key oncogenic signalling pathways.

show abstract

Targeting Hippo signaling in cancer: novel perspectives and therapeutic potential

Cited by 7 publications

References 261 publications

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

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

Molecular pathways and targeted therapies in head and neck cancers pathogenesis

Drug Repurposing: Exploring Potential Anti-Cancer Strategies by Targeting Cancer Signalling Pathways

Contact Info

Product

Resources

About