PHARMACOLOGICAL INHIBITION OF PDGF-C/NEUROPILIN-1 INTERACTION: A NOVEL STRATEGY TO REDUCE MELANOMA METASTATIC POTENTIAL
Description
Through a virtual screening strategy using a 3D drug library, our study allowed to identify drug candidates able to interfere with NRP-1 activation by PDGF-C and the consequent melanoma motility/invasiveness. Using experimental validation procedures, we demonstrated for the first time that gliclazide and entrectinib, at clinically achievable concentrations, selectively inhibited in vitro the migration of NRP-1 expressing and PDGF-C secreting melanoma cells as well as the intracellular signal transduction activated by the ligand/receptor interaction. Both gliclazide and entrectinib can be administered for long periods with few side effects; therefore, they might be safely associated with the current standard therapy for melanoma, i.e., BRAFi plus MEKi or ICIs, without significant increase in toxicity. Furthermore, entrectinib, due to its ability to cross the blood-brain barrier [64], might be useful in the presence of brain metastases, a common finding detected in patients with advanced melanoma. Further studies in in vivo models will be necessary to confirm the efficacy of such drug combinations on tumor growth and metastasis.