Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors

Int J Mol Sci. 2019 Aug 29;20(17):4235. doi: 10.3390/ijms20174235.


Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.

Keywords: BRAF; MAPK; PI3K; apoptosis; brain metastasis; combined treatment; melanoma.

MeSH terms

  • Aminopyridines / administration & dosage
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / prevention & control*
  • Brain Neoplasms / secondary
  • Cell Line, Tumor
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitogen-Activated Protein Kinases / metabolism*
  • Morpholines / administration & dosage
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridones / administration & dosage
  • Pyrimidinones / administration & dosage
  • Signal Transduction / drug effects*
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Treatment Outcome
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays


  • Aminopyridines
  • Morpholines
  • NVP-BKM120
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • trametinib
  • Mitogen-Activated Protein Kinases