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

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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. Clin Cancer Res; 23(21); 6629-39. ©2017 AACR.

Original languageEnglish
Pages (from-to)6629-6639
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number21
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols/administration & dosage
  • Apoptosis/drug effects
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Drug Resistance, Neoplasm/genetics
  • Gene Expression Regulation, Neoplastic/drug effects
  • Humans
  • Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors
  • Mice
  • Neuroblastoma/drug therapy
  • Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors
  • Pyrrolidines/administration & dosage
  • Sirolimus/administration & dosage
  • TOR Serine-Threonine Kinases/antagonists & inhibitors
  • Tumor Suppressor Protein p53/genetics
  • Xenograft Model Antitumor Assays
  • para-Aminobenzoates/administration & dosage

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