Figure 7. Model for acquired resistance of BRAF-ATCs to inhibition of the oncogenic driver.

ATCs are heavily infiltrated by immune suppressive tumor-associated macrophages. ATCs regress upon inhibition of BRAF^V600E expression or signaling, which is associated with a decrease in immunosuppressive myeloid cells. Recurrent disease is driven by mutations that reactivate MAPK signaling, primarily by Met amplification and concurrent cell-autonomous overexpression of the Met ligand Hgf. The recurrent cancer clones likely arise from cells with stem-like properties, and give rise to ATCs that exhibit focal transdifferentiation to cells with other lineage properties. The images depicting the different histologies of the recurrent tumors are those shown in Figure 1 or Supplemental Figure 5.