Fig. 7: Rac1-driven BRAFi-resistant melanoma cells respond to combinatorial inhibition of RAF/MEK and FAK.

A–J A375 and 451Lu cells, either vector control (VEC) or various Rac1-driven cell lines including Rac1 P29S-expressing cells, the A375 VRPP1-3 sublines, or A375 VAV1-expressing cells were treated with different combinations of the novel RAF/MEK clamp, VS-6766 (avutometinib) and the FAK inhibitors defactinib or VS-4718. Cell growth over time was measured via resazurin assay. While some cell lines displayed resistance to avutometinib alone, the combination of avutometinib and FAK inhibitors was able to control the growth of the cells. K, L Combined inhibition of RAF/MEK and FAK also controlled A375 Rac1 P29S cells growing on 3D collagen. Interestingly, cells expressing Rac1 P29S were also more sensitive to FAK inhibition as a monotherapy. See Supplementary Table S2 for area under the curve (AUC) statistical analysis of differences in growth curves compared to DMSO control.