Abstract: Melanoma is the deadliest form of skin cancer, and BRAFV600E is a driver mutation that promotes melanoma growth and survival. PLX4032 is the first effective compound in clinical use for the treatment of patients with mutant BRAFV600. However, resistance to PLX4032 develops quickly within months. Activation of a series of receptor tyrosine kinases, including the platelet-derived growth factor receptor (PDGFR), has been identified to be the underlying mechanism for development of resistance to PLX4032. In this work, we investigated the anticancer activity of tyrphostin AG1296, a PDGFR inhibitor, in melanoma, especially PLX4032-resistant melanoma. We found that tyrphostin AG1296 could effectively reduce the viability of both PLX4032-sensitive and PLX4032-resistant melanoma cells. There is an additive effect between tyrphostin AG1296 and PLX4032 in reducing cell viability. Tyrphostin AG1296 induced dramatic apoptosis in PLX4032-resistant cells, and also dramatically inhibited migration of PLX4032-resistant cells. Importantly, tyrphostin AG1296 significantly suppressed A375R tumor growth in vivo. This is the first report on the anticancer activity of tyrphostin AG1296 in melanoma. Tyrphostin AG1296 is a promising compound in the treatment of melanoma, especially for those who have developed resistance towards BRAF inhibitors, and might shed new light on melanoma therapy.
Keywords: melanoma, PLX4032, resistance, viability, apoptosis, migration