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.
Highlights
The p53 protein plays a central role in tumour suppression, by regulating the expression of numerous downstream target genes involved in cellular processes such as apoptosis, cell cycle arrest, differentiation and senescence
The concentration of RG7388 required to inhibit growth by 50% (GI50) was determined using XTT cell proliferation assays in a panel of neuroblastoma cell lines, including 5 p53 mutant and 16 p53 wt cell lines of varying MYCN, MDM2 and p14ARF status, together with the p53 wt MYCN-regulatable SHEP Tet21N cells (Table 1, Figure 1A, Supplementary Figure 1A)
This www.impactjournals.com/oncotarget study demonstrates for the first time the highly selective and potent in vitro anti-tumour activity of RG7388 as a single agent in p53 wt neuroblastoma of varying MYCN, MDM2 and p14ARF genetic status, resulting in p53 stabilisation and activation of the p53 pathway
Summary
The p53 protein plays a central role in tumour suppression, by regulating the expression of numerous downstream target genes involved in cellular processes such as apoptosis, cell cycle arrest, differentiation and senescence. Hoffmann-La Roche were the first to report potent and selective small molecule MDM2-p53 binding antagonists, the cis-imidazoline (Nutlin) compound series [3]. Nutlin-3 has been shown to stabilise p53 and activate the p53 pathway, inducing cell cycle arrest, www.impactjournals.com/oncotarget apoptosis, differentiation and/or senescence, in several p53 wt pre-clinical cancer models. The lead cis-imidazoline, RG7112, was subsequently the first of its class to enter clinical trials and despite demonstrating proofof-mechanism in adult MDM2-amplified liposarcoma patients [4], results from several Phase I trials indicated highly variable bioavailability, a poor tolerability to daily oral administration and thrombocytopenia as a doselimiting toxicity [5]. RG7388 is anticipated to enter paediatric early phase trials in the near future
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