C57BL/6 congenic mouse NRASQ61K melanoma cell lines are highly sensitive to the combination of Mek and Akt inhibitors in vitro and in vivo

Pigment Cell Melanoma Res. 2019 Nov;32(6):829-841. doi: 10.1111/pcmr.12807. Epub 2019 Jul 15.

Abstract

RAS is frequently mutated in various tumors and known to be difficult to target. NRASQ61K/R are the second most frequent mutations found in human skin melanoma after BRAFV600E . Aside from surgery, various approaches, including targeted therapies, immunotherapies, and combination therapies, are used to treat patients carrying NRAS mutations, but they are inefficient. Here, we established mouse NRASQ61K melanoma cell lines and genetically derived isografts (GDIs) from Tyr::NRASQ61K mouse melanoma that can be used in vitro and in vivo in an immune-competent environment (C57BL/6) to test and discover novel therapies. We characterized these cell lines at the cellular, molecular, and oncogenic levels and show that NRASQ61K melanoma is highly sensitive to the combination of Mek and Akt inhibitors. This preclinical model shows much potential for the screening of novel therapeutic strategies for patients harboring NRAS mutations that have limited therapeutic options and resulted in poor prognoses.

Keywords: MK-2206 2HCl; PD-0325901; S6; binimetinib; mouse model.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzimidazoles / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Shape / drug effects
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Melanocytes / drug effects
  • Melanocytes / pathology
  • Melanoma / pathology*
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Models, Biological
  • Monomeric GTP-Binding Proteins / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects

Substances

  • Benzimidazoles
  • Heterocyclic Compounds, 3-Ring
  • MK 2206
  • Protein Kinase Inhibitors
  • binimetinib
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase Kinases
  • Monomeric GTP-Binding Proteins
  • Nras protein, mouse