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MAPK-interacting kinases inhibition by eFT508 overcomes chemoresistance in preclinical model of osteosarcoma

Bin Huang1, Peicheng Jin1, Kaijun Yi1

  • 1Department of Orthopedics, Xiangyang No.1 People's Hospital, 36841Hubei University of Medicine, Xiangyang, China.

Human & Experimental Toxicology
|February 25, 2023
PubMed

Insights

eFT508, a MAPK-interacting kinase 1 and 2 (MNK1/2) inhibitor, effectively targets osteosarcoma by inhibiting growth and migration. It shows synergistic effects with paclitaxel, offering a promising therapeutic strategy for osteosarcoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • MAPK-interacting kinases 1 and 2 (MNK1/2) are emerging therapeutic targets in cancer.
  • Their role in osteosarcoma remains largely unexplored.
  • This study investigates MNK1/2 inhibition in osteosarcoma models.

Purpose of the Study:

  • To evaluate the efficacy of eFT508, a selective MNK1/2 inhibitor, in osteosarcoma.
  • To assess eFT508 as a single agent and in combination with paclitaxel.
  • To elucidate the underlying mechanisms of eFT508 action in osteosarcoma.

Main Methods:

  • In vitro studies using multiple osteosarcoma cell lines.
  • In vivo studies using preclinical osteosarcoma mouse models.
  • Assessment of cell growth, survival, migration, and protein translation inhibition (eIF4E phosphorylation).

Main Results:

  • eFT508 inhibited osteosarcoma cell growth, survival, and migration.
  • eFT508 demonstrated selectivity, with lower toxicity to normal osteoblasts.
  • In vivo, eFT508 non-toxic doses arrested tumor growth and blocked eIF4E phosphorylation.
  • eFT508 and paclitaxel exhibited synergistic effects in osteosarcoma cells.

Conclusions:

  • MNK1/2 inhibition is a viable therapeutic strategy for osteosarcoma.
  • eFT508 shows significant anti-osteosarcoma activity and selectivity.
  • eFT508, alone or combined with paclitaxel, represents a promising treatment candidate for osteosarcoma.
Keywords:
MNK1/2chemotherapyeFT508osteosarcomasynergism

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