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Dual targeting of melanoma translation by MNK/eIF4E and PI3K/mTOR inhibitors

Dorota Gil1, Marta Zarzycka1, Joanna Pabijan2

  • 1Medical Biochemistry, Jagiellonian University Medical College, ul. Kopernika 7, 31-034 Kraków, Poland.

Cellular Signalling
|June 2, 2023
PubMed

Insights

Combining PI3K/mTOR and Mnk inhibitors shows enhanced anti-melanoma effects. This dual-pathway inhibition may prevent drug resistance in melanoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Melanoma exhibits resistance to conventional chemotherapy, with limited efficacy of current targeted therapies.
  • Common melanoma mutations lead to hyperactivation of the mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR signaling pathways.
  • These activated pathways are crucial for oncogenic protein translation and represent potential therapeutic targets.

Purpose of the Study:

  • To investigate the mechanism of action of dactolisib (a PI3K/mTOR inhibitor) and CGP57380 (an Mnk inhibitor) in melanoma.
  • To evaluate the combined antitumor effects of these inhibitors on melanoma cell viability and invasiveness.
  • To explore the potential of simultaneous pathway inhibition in overcoming drug resistance.

Main Methods:

  • Utilized human melanoma cell lines (WM793 and 1205LU) with BRAFV600E mutation and PTEN loss.
  • Administered dactolisib (PI3K/mTOR inhibitor) and CGP57380 (Mnk inhibitor) individually and in combination.
  • Assessed effects on cell proliferation, migration, and invasiveness.

Main Results:

  • Both dactolisib and CGP57380 demonstrated inhibitory effects on melanoma cell proliferation and migration when used independently.
  • The combination therapy exhibited augmented anti-tumor effects compared to monotherapy.
  • Simultaneous inhibition of both PI3K/mTOR and Mnk pathways showed additional anti-melanoma benefits.

Conclusions:

  • Dual inhibition of PI3K/mTOR and Mnk pathways offers enhanced anti-melanoma activity.
  • This combination strategy may serve as a promising approach to prevent or overcome drug resistance in melanoma.
  • Further research into combined pathway inhibition is warranted for melanoma therapeutic development.
Keywords:
AMPKMNKMelanomaeIF2αeIF4EmTOR

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