Counteracting resistance to targeted therapy in melanoma by inhibiting discoidin domain receptors

Anti-BRAF plus an anti-MEK is currently used in first line for the management of patients presenting metastatic melanomas harboring the mutation. However, the main issue during targeted therapy is the acquisition of cellular resistance in 80% of the patients, which is associated with an increased metastasis due to the hyperactivation of MAP kinase pathway. Previous reports have indicated that Discoidin Domain Receptors (DDRs) 1 and 2 can activate this pathway. To study the role of DDRs in melanoma cell resistance to targeted therapy, we first determined that DDRs are overexpressed in vemurafenib resistant cells compared to sensitive cells. We demonstrated that DDRs depletion or inactivation by DDRs inhibitors such as dasatinib or CR-13542 reduces tumor cell proliferation, due to a decrease of MAP kinase pathway activity in resistant cells. Finally, we confirmed these results in a xenograft mouse model and show that DDRs could be new therapeutic targets in resistant patients with metastatic melanoma. We propose that dasatinib could be a second-line treatment after the bi-therapy in resistant patients overexpressing DDRs.