Sox9-dependent acquisition of a drug resistant "memory state" induces reciprocal expression of Sox6 and Sox7 in BRAF melanoma

In melanoma, SOX9 and SOX10 are markers of the mesenchymal and melanocytic state, respectively. Using a panel of BRAFV600E positive YUMM lines, we find that, following chronic vemurafenib treatment, SOX10 is lost whereas SOX9 is induced. Overexpression or knock-down of either SOX9 or SOX10 had no impact on vemurafenib sensitivity. However, we find that SOX9 is necessary to program a vemurafenib-resistance memory state following a drug holiday in vitro. RNA-Seq studies show that the loss of Sox10 represents an intermediate state that is accompanied by the loss of Sox6 and the induction of Sox7, Sox9 and other phenotype switching markers. However, SOX7 expression is not sufficient to induce vemurafenib resistance. Upon acquired drug resistance, we observed differential chromatin accessibility in the Sox9 and Sox10 upstream regions, supporting their activation and repression, respectively. Overall, our data show that the loss of SOX10 and SOX9 induction are critical to program drug resistance. Furthermore, we show that the YUMM cell lines represent a good murine model to investigate transitions to an acquired drug resistant state.