In melanoma, the MAPK and the PI3K signaling pathways are commonly altered, and inhibiting one of them often upregulates the other, leading to resistance. Thus, treatment targeting both pathways is a promising strategy.
We have 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 showed that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumour 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.
For more information, see the published article here.