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Translational Therapeutics

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

Abstract

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.

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Fig. 1: Regorafenib reduces neuroblastoma cell viability and xenograft tumour growth.
Fig. 2: Regorafenib induces neuroblastoma cell apoptosis.
Fig. 3: Regorafenib inhibits targets in neuroblastoma cells.
Fig. 4: Regorafenib treatment alters protein expression and phosphorylation in neuroblastoma cells.
Fig. 5: Efficacy of regorafenib combined with 13-cis-retinoic acid in neuroblastoma cells.
Fig. 6: Regorafenib combined with 13-cis-retinoic acid alters protein expression and phosphorylation in neuroblastoma cells.

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Acknowledgements

Portions of this work have been published as an abstract (Subramonian et al., J Clin Oncol 2017; 35:10553) and presented as a poster at the American Society of Clinical Oncology Annual Meeting in June of 2017.

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D.S.: conceptualisation, data curation, formal analysis, investigation, methodology, validation and writing—review and editing. N.P.: data curation, formal analysis, investigation, validation, writing—original draft and writing—review and editing. H.R.: data curation, investigation, validation and writing—review and editing. S.F.: data curation, investigation, validation and writing—review and editing. Y.H.: data curation, investigation, validation and writing—review and editing. J.Z.: data curation, formal analysis, investigation, validation, writing—original draft and writing—review and editing. K.M.: data curation, formal analysis, investigation, supervision, validation and writing—review and editing. Q.M.: data curation, formal analysis, investigation, validation and writing—review and editing. S.H.: data curation, formal analysis, investigation, supervision, validation and writing—review and editing. J.L.: data curation, investigation, validation and writing—review and editing. P.E.Z.: conceptualisation, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, supervision, validation, writing—original draft and writing—review and editing.

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Correspondence to Peter E. Zage.

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All animal experiments were performed in accordance with relevant guidelines and regulations, and all mice were treated according to protocols approved by the Institutional Animal Care and Use Committee at UCSD; no human subjects were included in these experiments.

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This study was supported by Bayer, AG with study drug and research funding (to P.E.Z.). The authors declare there are no other competing interests.

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This study was supported by Bayer, AG with study drug and research funding (to P.E.Z.). This work was supported in part by a Cancer Prevention & Research Institute of Texas Proteomics & Metabolomics Core Facility Support Award (RP170005) (to S.H.) and an NCI Cancer Center Support Grant to the Antibody-based Proteomics Core/Shared Resource at Baylor College of Medicine (P30CA125123) (to S.H.).

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Subramonian, D., Phanhthilath, N., Rinehardt, H. et al. Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Br J Cancer 123, 568–579 (2020). https://doi.org/10.1038/s41416-020-0905-8

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