Despite remarkable efforts, metastatic melanoma still presents with significant mortality. Recently, mono-chemotherapies are increasingly replenished by more cancer specific combination therapies involving death ligands and drugs interfering with cellular life and death signaling. Still, metastatic melanoma remains a fatal disease because tumors rapidly develop resistance to novel therapies thereby regaining tumorigenic capacity. By combining statistical and network modeling and systems analysis with basic research and clinical data we aim to elucidate mechanisms of therapy-resistance of melanoma and to identify combinatorial systems biomarkers to prognosticate treatment responsiveness of BRAF mutated metastatic melanoma to BRAF (dabrafenib) /MEK (trametenib) inhibitors and to TRAIL death receptor agonists. Our proposal builds on a substantial amount of very promising preliminary data, and will set an example for how innovative systems-level strategies can be exploited to address urgent clinical needs for developing predictive assays for existing drugs and new drug combinations. The research team comprises academic, clinical and private partners, and provides the framework that is required for the integration of validated systems tools into clinical trials and clinical practice to benefit patients in the short term.