To model the contribution of the ECM in melanoma cell responses to BRAF and MEK inhibition, we generated fibroblast‐derived 3D ECM from melanoma‐associated fibroblasts (MAFs), which were isolated from patient‐derived biopsies and analyzed the MMDR mechanism with the aim to identify novel opportunities for microenvironment‐targeted therapies. The gene discussed is BRAF; the disease is melanoma.