The multikinase inhibitor RXDX-105 is effective against neuroblastoma<i>in vitro</i>and<i>in vivo</i>

Flynn, Sean; Lesperance, Jacqueline; Macias, Andrew; Phanhthilath, Nikki; Paul, Megan; Kim, Jong Wook; Tamayo, Pablo; Zage, Peter E.

doi:10.18632/oncotarget.27259

Cited by 9 publications

(11 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In parallel, Zhang et al [59] characterized the effect of another RET inhibitor, cabozantinib (XL184), on in vitro and in vivo neuroblastoma paradigms. Subsequent studies from the same group found comparable results when using the small-molecule RET/ multikinase inhibitor RXDX-105 [60] or the RET/multikinase inhibitor regorafenib (BAY 73-4506) [61]. Notably, the effect of regorafenib on in vitro and in vivo neuroblastoma models had been previously reported by Chen et al [62].…”

Section: Retmentioning

confidence: 64%

Systematic review of the receptor tyrosine kinase superfamily in neuroblastoma pathophysiology

Rozen

Shohet

2021

Cancer Metastasis Rev

View full text Add to dashboard Cite

Background Neuroblastoma is a devastating disease accounting for 15% of all childhood cancer deaths. Yet, our understanding of key molecular drivers such as receptor tyrosine kinases (RTKs) in this pathology remains poorly clarified. Here, we provide a systematic analysis of the RTK superfamily in the context of neuroblastoma pathogenesis. Methods Statistical correlations for all RTK family members’ expression to neuroblastoma patient survival across 10 independent patient cohorts were annotated, synthesized, and ranked using the R2: Genomics Analysis and Visualization Platform. Gene expression of selected members across different cancer cell lines was further analyzed in the Cancer Cell Line Encyclopedia, part of the Cancer Dependency Map portal (depmap portal (http://depmap.org)). Finally, we provide a detailed literature review for highly ranked candidates. Results Our analysis defined two subsets of RTKs showing robust associations with either better or worse survival, constituting potential novel players in neuroblastoma pathophysiology, diagnosis, and therapy. We review the available literature regarding the oncogenic functions of these RTKs, their roles in neuroblastoma pathophysiology, and potential utility as therapeutic targets. Conclusions Our systematic analysis and review of the RTK superfamily in neuroblastoma pathogenesis provides a new resource to guide the research community towards focused efforts investigating signaling pathways that contribute to neuroblastoma tumor establishment, growth, and/or aggressiveness and targeting these druggable molecules in novel therapeutic strategies.

show abstract

Section: Retmentioning

confidence: 64%

Systematic review of the receptor tyrosine kinase superfamily in neuroblastoma pathophysiology

Rozen

Shohet

2021

Cancer Metastasis Rev

View full text Add to dashboard Cite

show abstract

“…Continuous live-cell imaging was performed as previously described. 31 Briefly, neuroblastoma cells were plated in 96-well plates at seeding densities between 10,000 and 25,000 cells/well and treated with regorafenib alone and in combination with 13- cis -retinoic acid as above. The plates were placed into the IncuCyte ® Zoom TM continuous live-cell imaging system (Essen Bioscience, Ann Arbor, MI), and phase-contrast images were taken every 6 h at 10× magnification for 72 h. Cell confluence was calculated using IncuCyte ® analysis software.…”

Section: Methodsmentioning

confidence: 99%

Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis. Methods We evaluated neuroblastoma cells treated with regorafenib for cell viability and confluence, and analysed treated cells for apoptosis and cell cycle progression. We evaluated the efficacy of regorafenib in vivo using an orthotopic xenograft model. We evaluated regorafenib-mediated inhibition of kinase targets and performed reverse-phase protein array (RPPA) analysis of neuroblastoma cells treated with regorafenib. Lastly, we evaluated the efficacy and effects of the combination of regorafenib and 13-cis-retinoic acid on intracellular signalling. Results Regorafenib treatment resulted in reduced neuroblastoma cell viability and confluence, with both induction of apoptosis and of cell cycle arrest. Regorafenib treatment inhibits known receptor tyrosine kinase targets RET and PDGFRβ and intracellular signalling through the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Regorafenib is effective against neuroblastoma tumours in vivo, and the combination of regorafenib and 13-cis-retinoic acid demonstrates enhanced efficacy compared with regorafenib alone. Conclusions The effects of regorafenib on multiple intracellular signalling pathways and the potential additional efficacy when combined with 13-cis-retinoic acid represent opportunities to develop treatment regimens incorporating regorafenib for children with neuroblastoma.

show abstract

“…The human neuroblastoma cell lines (SK-N-AS; SK-N-BE(2); SK-N-SH; SH-SY5Y; IMR-32; SH-EP) used in this study have been previously utilized by our laboratory (45)(46)(47) and were purchased from American Type Culture Collection (ATCC, www.atcc.org) or were generously provided by Susan Cohn (The University of Chicago Children's Hospital, Chicago, IL) or John Maris (Children's Hospital of Philadelphia, Philadelphia, PA). HEK 293T cells were purchased from ATCC.…”

Section: Cells and Culture Conditionsmentioning

confidence: 99%

UBE4B interacts with the ITCH E3 ubiquitin ligase to induce Ku70 and c-FLIPL polyubiquitination and enhanced neuroblastoma apoptosis

Clorennec

Subramonian

Huo

et al. 2023

Preprint

View full text Add to dashboard Cite

Expression of the UBE4B ubiquitin ligase is strongly associated with neuroblastoma patient outcomes, but the functional roles of UBE4B in neuroblastoma pathogenesis are not known. We evaluated interactions of UBE4B with the E3 ubiquitin ligase ITCH/AIP4 and the effects of UBE4B expression on Ku70 and c-FLIPL ubiquitination and proteasomal degradation by co-immunoprecipitation and Western blots. We also evaluated the role of UBE4B in apoptosis induced by histone deacetylase (HDAC) inhibition using Western blots. UBE4B binding to ITCH was mediated by WW domains in the ITCH protein. ITCH activation led to ITCH-UBE4B complex formation and recruitment of Ku70 and c-FLIPL via ITCH WW domains, followed by Ku70 and c-FLIPL Lys48/Lys63 branched polyubiquitination and proteasomal degradation. HDAC inhibition induced Ku70 acetylation, leading to release of c-FLIPL and Bax from Ku70, increased Ku70 and c-FLIPL Lys48/Lys63 branched polyubiquitination via the ITCH-UBE4B complex, and induction of apoptosis. UBE4B depletion led to reduced polyubiquitination and increased levels of Ku70 and c-FLIPL and to reduced apoptosis induced by HDAC inhibition via stabilization of c-FLIPL and Ku70 and inhibition of caspase 8 activation. Our results have identified novel interactions and novel targets for UBE4B ubiquitin ligase activity and a direct role of the ITCH-UBE4B complex in responses of neuroblastoma cells to HDAC inhibition, suggesting that the ITCH-UBE4B complex plays a critical role in responses of neuroblastoma to therapy and suggesting a potential mechanism underlying the association of UBE4B expression with neuroblastoma patient outcomes.

show abstract

The multikinase inhibitor RXDX-105 is effective against neuroblastomain vitroandin vivo

Cited by 9 publications

References 34 publications

Systematic review of the receptor tyrosine kinase superfamily in neuroblastoma pathophysiology

Systematic review of the receptor tyrosine kinase superfamily in neuroblastoma pathophysiology

Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways

UBE4B interacts with the ITCH E3 ubiquitin ligase to induce Ku70 and c-FLIPL polyubiquitination and enhanced neuroblastoma apoptosis

Contact Info

Product

Resources

About