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Preclinical Therapeutic Efficacy of RAF/MEK/ERK and IGF1R/AKT/mTOR Inhibition in Neuroblastoma

Affiliations
  • 1Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, NIH, 8560 Progress Drive, Frederick, MD 21701, USA.
  • 2Early Translation Branch, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • 3Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA.
  • 4Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Services, Bethesda, MD 20814, USA.
  • 5Animal Research Technical Support, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
  • 6Small Animal Imaging Program, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
  • 7Collaborative Protein Technology Resource, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • 8Molecular Histopathology Laboratory, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.

Published on:

July 13, 2024

Abstract

Activating mutations in the RAS/MAPK pathway are observed in relapsed neuroblastoma. Preclinical studies indicate that these tumors have an increased sensitivity to inhibitors of the RAS/MAPK pathway, such as MEK inhibitors. MEK inhibitors do not induce durable responses as single agents, indicating a need to identify synergistic combinations of targeted agents to provide therapeutic benefit. We previously showed preclinical therapeutic synergy between a MEK inhibitor, trametinib, and a monoclonal antibody specific for IGF1R, ganitumab in RAS-mutated rhabdomyosarcoma. Neuroblastoma cells, like rhabdomyosarcoma cells, are sensitive to the inhibition of the RAS/MAPK and IGF1R/AKT/mTOR pathways. We hypothesized that the combination of trametinib and ganitumab would be effective in RAS-mutated neuroblastoma. In this study, trametinib and ganitumab synergistically suppressed neuroblastoma cell proliferation and induced apoptosis in cell culture. We also observed a delay in tumor initiation and prolongation of survival in heterotopic and orthotopic xenograft models treated with trametinib and ganitumab. However, the growth of both primary and metastatic tumors was observed in animals receiving the combination of trametinib and ganitumab. Therefore, more preclinical work is necessary before testing this combination in patients with relapsed or refractory RAS-mutated neuroblastoma.

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