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2 p., Introduction The BRAFV600E mutation in melanoma is generally associated with activation of the MAPK/ERK signaling pathway, leading to tumor cell proliferation. Targeted therapy with combined BRAFV600E and MEK inhibitors has improved patient survival, but resistance to this treatment is very frequent and represents a serious clinical challenge. Resistance can be intrinsic or can be based on newly-acquired genetic alterations. Moreover, drug tolerant/persister (DTP) clones arising without genetic changes from tumor cells that adapt and survive the initial phases of therapy, can be another source of resistance. The aim of our study is to characterize the mechanisms of resistance to MAPK-targeted therapy in melanoma., Material and Methods We have used the mouse melanoma YUMM cell model to in vitro and in vivo (C57BL/6 mice) generate cells resistant to combined BRAF and MEK inhibitors. Both putative DTP and resistant cell populations have been selected from the in vitro and in vivo platforms, and cell survival and proliferation, and cell signaling and function are being investigated., Results and Discussions DTP and resistant cells display significant changes in growth and in several signaling properties and transition markers, and potential gene differences are currently examined byRNAseq and their functional implications investigated., Conclusion Our in vitro and in vivo models represent useful platforms to mechanistically study drug adaptation and resistance mechanisms in DTP and resistant melanoma cell populations, as well as a system to assess new inhibitors targeting these populations.