p53 nongenotoxic activation and mTORC1 inhibition lead to effective combination for neuroblastoma therapy

Myrthala Moreno-Smith, Anna Lakoma, Zaowen Chen, Ling Tao, Kathleen A. Scorsone, Linda Schild, Kevin Aviles-Padilla, Rana Nikzad, Yankai Zhang, Rikhia Chakraborty, Jan J. Molenaar, Sanjeev A. Vasudevan, Vivien Sheehan, Eugene S. Kim, Silke Paust, Jason M. Shohet, Eveline Barbieri

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

19 Citaten (Scopus)

Samenvatting

Purpose: mTORC1 inhibitors are promising agents for neuroblastoma therapy; however, they have shown limited clinical activity as monotherapy, thus rational drug combinations need to be explored to improve efficacy. Importantly, neuroblastoma maintains both an active p53 and an aberrant mTOR signaling. Experimental Design: Using an orthotopic xenograft model and modulating p53 levels, we investigated the antitumor effects of the mTORC1 inhibitor temsirolimus in neuroblastoma expressing normal, decreased, or mutant p53, both as single agent and in combination with first- and second-generation MDM2 inhibitors to reactivate p53. Results: Nongenotoxic p53 activation suppresses mTOR activity. Moreover, p53 reactivation via RG7388, a second-generation MDM2 inhibitor, strongly enhances the in vivo antitumor activity of temsirolimus. Single-agent temsirolimus does not elicit apoptosis, and tumors rapidly regrow after treatment suspension. In contrast, our combination therapy triggers a potent apoptotic response in wild-type p53 xenografts and efficiently blocks tumor regrowth after treatment completion. We also found that this combination uniquely led to p53-dependent suppression of survivin whose ectopic expression is sufficient to rescue the apoptosis induced by our combination. Conclusions: Our study supports a novel highly effective strategy that combines RG7388 and temsirolimus in wild-type p53 neuroblastoma, which warrants testing in early-phase clinical trials.

Originele taal-2Engels
Pagina's (van-tot)6629-6639
Aantal pagina's11
TijdschriftClinical Cancer Research
Volume23
Nummer van het tijdschrift21
DOI's
StatusGepubliceerd - 1 nov. 2017
Extern gepubliceerdJa

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