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Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma

Lookup NU author(s): Dr Lindi Chen, Emeritus Professor Herbie Newell, Emeritus Professor John LunecORCiD, Professor Deborah TweddleORCiD

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Abstract

Neuroblastoma is a predominantly p53 wild-type (wt) tumour and MDM2-p53 antagonists offer a novel therapeutic strategy for neuroblastoma patients. RG7388 (Roche) is currently undergoing early phase clinical evaluation in adults. This study assessed the efficacy of RG7388 as a single-agent and in combination with chemotherapies currently used to treat neuroblastoma in a panel of neuroblastoma cell lines. RG7388 GI₅₀ concentrations were determined in 21 p53-wt and mutant neuroblastoma cell lines of varying MYCN, MDM2 and p14^ARF status, together with MYCN-regulatable Tet21N cells. The primary determinant of response was the presence of wt p53, and overall there was a >200-fold difference in RG7388 GI₅₀ concentrations for p53-wt versus mutant cell lines. Tet21N MYCN+ cells were significantly more sensitive to RG7388 compared with MYCN- cells. Using median-effect analysis in 5 p53-wt neuroblastoma cell lines, selected combinations of RG7388 with cisplatin, doxorubicin, topotecan, temozolomide and busulfan were synergistic. Furthermore, combination treatments led to increased apoptosis, as evident by higher caspase-3/7 activity compared to either agent alone. These data show that RG7388 is highly potent against p53-wt neuroblastoma cells, and strongly supports its further evaluation as a novel therapy for patients with high-risk neuroblastoma and wt p53 to potentially improve survival and/or reduce toxicity.

Publication metadata

Author(s): Chen L, Rousseau RF, Middleton SA, Nichols GL, Newell DR, Lunec J, Tweddle DA

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2015

Volume: 6

Issue: 12

Pages: 10207-10221

Online publication date: 10/03/2015

Acceptance date: 17/02/2015

Date deposited: 17/04/2015

ISSN (electronic): 1949-2553

Publisher: Impact Journals LLC

URL: https://doi.org/10.18632/oncotarget.3504

DOI: 10.18632/oncotarget.3504

PubMed id: 25844600

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